Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases

ABSTRACT

There is disclosed a genus of non-peptidyl compounds, wherein said compounds are VLA-4 inhibitors useful in treating inflammatory, autoimmune, and respiratory diseases, and wherein said compounds comprise a compound of Formula (1.0.0):                    
     and pharmaceutically acceptable salts and other prodrug derivatives thereof, wherein: A is (C 1 -C 6 ) alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl as defined herein; where said alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with 0 to 3 R 9 ; or is a member selected from the group consisiting of the following radicals: A 1 -NHC(═O)NH-A 2 -, A 1 -NHC(═O)O-A 2 -, A 1 -OC(═O)NH-A 2 -, A 1 -NHSO 2 NH-A 2 -, A 1 -NHC(═O)-A 2 -, A 1 -C(═O)NH-A 2 -, A 1 -NHSO 2 -A 2 -, A 1 SO 2 NH-A 2 -, A 1 -(CH 2 ) r O-A 2 -, A 1 -O(CH 2 ) r A 2 -, A 1 -(CH 2 ) r A 2 -, where A 1  is aryl and A 2  is aryl or pyridyl where said aryl or pyridyl group is substituted with 0 to 3 R 9 ; —B is oxazolinyl or isoxazolinyl which may be optionally substituted with R 9 ; R 2  and R 3  are each independently selected from the group consisting of hydrogen and (C 1 -C 6 ) alkyl substituted with 0 to 3 R 13 ; -R 4  is hydrogen; or (C 1 -C 6 ) alkyl optionally substituted with R 13 ; and the remaining variables are defined as set forth in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division of copending U.S. Ser. No. 09/747,246, filed Dec. 21,2000, which claims priority to U.S. Provisional Application No.60/173,260 filed Dec. 28,1999.

REFERENCE TO CO-PENDING APPLICATIONS

Reference is made herein to application U.S. Ser. No. 09/403846 filedOct. 26, 1999; which is a continuation-in-part of U.S. Ser. No.09/338832 filed Jun. 23, 1999; which is a continuation of provisionalapplication U.S. Ser. No. 60/091180 filed Jun. 30, 1998, and nowabandoned; and reference is further made to corresponding InternationalApplication PCT/IB99/00973 filed May 31, 1999, and published as WO99/00477 on Jan. 6, 2000.

The present invention relates to compounds which are non-peptidyl instructure and active as potent inhibitors of the binding of very lateantigen-4 (VLA-4; α₄β₁; CD49d/CD29) to proteins such as vascular celladhesion molecule-1 (VCAM-1), the HepII/IIICS domain (CS-1 region) offibronectin and osteopontin. As such they are useful in the inhibitionof cell adhesion and consequent or associated pathogenic processessubsequently mediated by VLA-4. The compounds and pharmaceuticalcompositions of this invention may be used in the treatment of manyinflammatory, autoimmune and respiratory diseases, especially asthma.

BACKGROUND OF THE INVENTION

One of the most fundamental processes necessary for normal host defenceis the regulated trafficking of leukocytes out of the vasculature. Thissystem is designed to allow normal recirculation of leukocytes, yetbecause it enables the rapid extravasation of leukocytes at sites ofinjury it is one of the central pathogenic mechanisms of inflammatory,respiratory and autoimmune diseases in mammals. Cell adhesion is a keyfactor in this process, and it is particularly relevant to the presentinvention regarding the cell/cell and cell/matrix binding ofhematopoietic cells containing VLA-4.

VLA-4 is a member of a superfamily of cell surface macromolecularreceptors called integrins, which are non-covalent heterodimericcomplexes consisting of an α subunit and a β subunit (Hemler, Ann. Rev.Immunol., 8, p.365, 1990). Eighteen different α subunits have beenidentified and labeled α₁-α₁₀, α_(L), α_(M), α_(x), α_(d), α_(LRI),α_(IIB), α_(V), and α_(E); while eight different β subunits have beenidentified and labeled β₁-β₈. Each integrin molecule can be categorizedinto a subfamily based on the type of its α and β subunits. The α₄β₁integrin, VLA-4, is an integrin constitutively expressed by allleukocytes (e.g., monocytes, lymphocytes, basophils, eosinophils, mastcells and macrophages) except polymorphonuclear leukocytes. The bindingof this integrin to one of its ligands has a number of known celladhesion and activation functions (Hemler, Ann. Rev. Immunol., 8, p.365,1990; Walsh et al., Clin. and Exp. Allergy, 25, p. 1128, 1995; Huhtalaet al., J. Cell Biol., 129, p. 867, 1995). In particular, it is areceptor for the cytokine-inducible endothelial cell surface proteinknown as vascular cell adhesion molecule-1 (VCAM-1), for thealternatively spliced forms of the extracellular matrix proteinfibronectin (FN) containing the CS-1 domain (Ruegg et al., J. CellBiol., 177, p. 179, 1991; Wayner et al., J. Cell Biol., 105, p. 1873,1987; Kramer et al., J. Biol. Chem., 264, p.4684, 1989; Gehlsen et al.,Science, 24, p. 1228, 1988) and for the extracellular matrix proteinosteopontin (Bayless, K. I. et al. J. Cell Science, 111, p. 1165-1174,1998). The importance of VLA-4 cell adhesion interactions has beenestablished by the use of specific monoclonal antibody (mAb) antagonistsof the a subunit of VLA-4, which have demonstrated that inhibitors ofVLA-4 dependent cell adhesion prevent or inhibit numerous inflammatory,respiratory and autoimmune pathological conditions (Chisholm et al.,Eur. J. Immunol., 23, p. 682, 1993; Lobb et al., J. Clin. Invest, 94, p.1722, 1994; Richards et al., Am. J. Respir. Cell Mol. Biol., 15, p.172,1996; Soiluhanninen et al., J. Neuroimmunol., 72, p. 95, 1997; Sagara etal., Int. Arch. Allergy Immunol., 112, p.287, 1997; Fryer et al., J.Clin. Invest., 99, p. 2036, 1997). In addition, confirmation that thispathological processes can be inhibited with agents other thanantibodies has been observed in animal models following treatment with asynthetic CS-1 peptide or a small molecule peptide inhibitor of VLA-4(Ferguson et al., Proc. Natl. Acad. Sci., 88, p.8072, 1991; Wahl et al.,J. Clin. Invest., 94, p.655, 1994; Molossi et al., J. Clin. Invest., 95,p.2601, 1995; Abraham et al., Am. J. Respir. Crit. Care Med., 156, p.696, 1997; Jackson et al., J. Med. Chem., 40, p. 3359, 1997).

3.0 Description of the State of the Art

The investigation of mAb and peptide VLA-4 antagonists in the art hasalready been noted above. In defining the binding site for α₄β₁ it hasbeen observed that lymphoid cells can bind to two different sites onfibronectin (Bernardi et al., J. Cell Biol., 105, p. 489, 1987). Onecomponent of this cell binding activity has previously been identifiedas the tripeptide Arg-Gly-Asp (RGD) that binds to the integrin α₅β₁(VLA5). Subsequently, the minimum amino acid sequence required to bindand antagonize the activity of VLA-4 on leukocytes to the alternativelyspliced site in fibronectin was determined (Humphries et al., J. Biol.Chem., 266, p.6886, 1987; Garcia-Pardo et al., J. Immunol., 144, p.3361,1990; Komoriya et al., J. Biol. Chem., 266, p. 15075, 1991). It has beendiscovered that the VLA-4 binding domain in the CS-1 region offibronectin (FN) comprises the octapeptide:Glu-Ile-Leu-Asp-Val-Pro-Ser-Thr, as well as two overlappingpentapeptides: Glu-Ile-Leu-Asp-Val and Leu-Asp-Val-Pro-Ser. All of thesepeptides inhibit FN-dependent cell adhesion, leading to the earlyconclusion that the minimal amino acid sequence required for inhibitionwould be Leu-Asp-Val (LDV). In fact the LDV minimal inhibitory sequencehas been observed to be equally effective as the full length CS-1fragment in binding the activated form of VLA-4 (Wayner et al., J. CellBiol., 116, p. 489, 1992).

Various integrins are believed to bind to extracellular matrix proteinsat an Arg-Gly Asp (RGD) recognition site. RGD based cyclic peptides havebeen made that are said to be able to inhibit both α₄β₁ and α₅β₁ bindingto FN (Nowlin et al., J. Biol. Chem., 268, p. 20352, 1993;PCT/US91/04862) even though the primary recognition on FN for α4β1 isLDV. The cyclic peptide may be represented by Formula (0.0.1):

where TPro denotes 4-thioproline.

Other peptidyl inhibitors of VLA-4 are those referred to in Arrhenius etal., “CS-1 Peptidomimetics,” WO 95/15973, which is assigned to the CytelCorporation and is related to the two U.S. patents noted below. Arepresentative compound of the type described is the peptide of Formula(0.0.2):

N-Phenylacetyl-Leu-Asp-Phe-NCy³  (0.0.2)

wherein NCy³ is selected from, inter alia, morpholinamido;thiomorpholinamido; 4-(thiadioxo)piperidinamido; andD-2-(carboxamide)-pyrrolidinamido; piperidinamido; and substitutedpiperidinamido.

WO 95/15973 . . . U.S. Pat. No. 5,821,231 . . . U.S. Pat. No. 5,936,065. . . Cytel Corporation

Further work by Arrhenius et al. involving cyclic CS-1 peptidomimeticsis described in WO 96/06108 assigned to the Cytel Corporation, which isrelated to the U.S. patent noted below.

WO 96/06108 . . . U.S. Pat. No. 5,869,448 . . . Cytel Corporation

The Arrhenius group has also discovered non-peptidal inhibitors of VLA-4dependent cell binding as described in He et al., WO 98/42656. Theinhibitors therein described are of the general Formula (0.0.3):

A typical inhibitor is that represented by Formula (0.0.4):

WO 98/42656 . . . Cytel Corporation

The Leu-Asp-Val tripeptide has been used as the core of a group ofinhibitors of VLA-4 dependent cell adhesion described in Adams et al. WO96/22966, which is assigned to Biogen, Inc. These inhibitors may berepresented by Formula (0.0.5):

where R¹ may be 4-(N′-(2-methylphenyl)urea)phenylmethyl; Y may be C═O;R² may be H; R³ may be iso-butyl; and R¹⁴ may be 1,3-benzodioxol-5-yl.An example of a typical inhibitor of this type is that of Formula(0.0.6):

WO 96/22966 . . . Biogen, Inc.

The Adams group has also discovered semi-peptidic cell adhesioninhibitors for the treatment of inflammation and autoimmune disease,described in Lin et al., WO 97/03094. These inhibitors may berepresented by Formula (0.0.7):

Z-(Y¹)-(Y²)-(Y³)_(n)-X  (0.0.7)

where Z may be 4-(N′-(2-methylphenyl)urea)phenylacetyl;(Y¹)-(Y²)-(Y³)_(n) represents a series of amino acids forming a peptidechain; and X may be OH. A typical inhibitor of this type is shown inFormula (0.0.8):

WO 97/03094 . . . Biogen, Inc.

The Adams group has also asserted, in Zheng et al., WO 98/04247, thediscovery that existing IIb/IIIa integrin inhibitory compounds may beconverted into VLA-4 inhibitory compounds, and that IIb/IIIa inhibitorycompounds can be made by combining a unique VLA-4 integrin scaffold witha IIIb/IIIa specificity determinant. These cell adhesion inhibitors maybe viewed as comprising a compound of the formula: A-B, where Acomprises a VLA-4 specificity determinant which does not impartsignificant IIb/IIIa integrin inhibitory activity, and B is an integrinscaffold derived from a IIb/IIIa inhibitor. A three dimensionalpharmacophore model of a compound having VLA-4 inhibitory activity isalso described. Representative of the inhibitors thus derived are thecompounds of Formulas (0.0.9) and (0.0.10):

WO 98/04247 . . . Biogen, Inc.

See also Singh et al., WO 98/04913, which refers to a three dimensionalpharmacophore model of a compound having VLA-4 inhibitory activity,comprising features defined by a table of tolerances and threedimensional coordinates x, y, and z. The following compound,representative of those referred to, may be represented by Formula(0.0.11):

WO 98/04913 . . . Biogen, Inc.

Another type of VLA-4 dependent cell adhesion inhibitor is thatdescribed in Head et al., “Anti-inflammatory Tyrosine Derivatives”, WO98/54207, which may be represented by general Formula (0.0.12):

where R¹ is an optionally substituted alkyl or aromatic group; X² is—C(═O)—; —C(═O)O—; —C(═O)NH—; or —S(═O)₂—; and R⁷ is an optionallysubstitutued alkyl or aryl group. A compound typical of this type ofinhibitor may be represented by Formula (0.0.13):

WO 98/54207 . . . Celltech Therapeutics Ltd.

The Head group has also discovered a related group of VLA-4 dependentcell adhesion inhibitors, described in Head et al., “PhenylalanineDerivatives Useful As Pharmaceutical Agents,” WO 99/37618, which are ofthe general Formula (0.0.14):

where L′ is a linker atom or group; A is a chain—[C(R⁷)(R⁸)]_(p)—Y—[C(R⁹)(R¹⁰)]_(q)—; and L² is a linker group selectedfrom —C(═O)—; —C(═O)O—; —C(═S)—; —S(═O)₂, or —C(═O)N(R¹¹)—. An exampleof this type of inhibitor is that of a compound of Formula (0.0.15):

WO 99/35163 . . . Celltech Therapeutics, Ltd.

Another closely related group of VLA-4 inhibitors discovered by the Headgroup is described in Head et al., “Novel Phenylalanine DerivativesUseful as Integrin Antagonists,” WO 99/37618, which is characterized bygeneral Formula (0.0.16):

A representative example of these inhibitory compounds is that ofFormula (0.0.17):

WO 99/37618 . . . Celltech Therapeutics, Ltd.

A still further related group of compounds discovered by the Head groupto be inhibitors of VLA-4 dependent cell adhesion is described in Headet al., “Phenylalanine Derivatives As Inhibitors of Alpha4 Integrins,”WO 99/43642, and may be characterized by general Formula (0.0.18):

Inhibitors of the type described are illustrated in Formula (0.0.19):

WO 99/43642 . . . Celltech Therapeutics, Ltd.

Early work in the discovery of inhibitors of VLA-4 dependent celladhesion has also been done by Pleiss and Thorsett and their co-workers,e.g., as described in Thorsett et al., “Inhibitors of LeukocyteAdhesion,” WO 96/01544 assigned to Athena Neurosciences, Inc. Theseinhibitors comprise inhibitors that block cellular adhesion mediated byVLA-4 and they are used to treat a number of inflammatory diseases,especially inflammatory brain disorders.

Non-peptide, i.e., small molecule inhibitors of VLA-4 have also beendiscovered by the Pleiss and Thorsett group, e.g., as described inThorsett, “Carbamoyloxy Compounds Which Inhibit Leukocyte AdhesionMediated by VLA-4,” WO 99/06390 assigned to Athena Neurosciences, Inc.Inhibitors of this type may be represented by general Formula (0.0.20):

where R¹ is alkyl, aryl, cycloalkyl, heterocyclic, or heteroaryl, all ofwhich are optionally substituted; R² is defined similarly to R¹ and maybe combined with it and the —S(═O)₂-moiety to form an optionallysubstituted heterocyclic group; R³ is defined similarly to R¹ and isoptionally taken together with the nitrogen atom bound to R² and thecarbon atom bound to R³ to form an optionally substituted heterocyclicgroup; R⁷ is —H or alkyl; Ar is optionally substituted aryl orheteroaryl; and R⁵ is —O—Z—NR⁸R^(8′) or —O—Z—R¹² where Z is —C(═O) or—S(═O)₂, R⁸ and R^(8′) are —H, or optionally substituted alkyl,cycloalkyl or hetercyclic, or R⁸ and R^(8′) may be joined to form anoptionally substituted heterocycle, and R¹² is optionally substitutedheterocycle.

A representative example of the above-described VLA-4 inhibitors is thecompound of Formula (0.0.21):

WO 99/06390 . . . Athena Neurosciences, Inc.

In Yednock and Pleiss “Alpha-9 Integrin Antagonists andAnti-inflammatory Compositions thereof,” WO 99/06391 assigned to AthenaNeurosciences, Inc., there is described the use of the inhibitorycompounds of above-mentioned WO 99/06390 in methods of treatingdisorders that involve binding of α-9 integrin, particularly adhesionmacrophages or neutrophils. Disorders said to be susceptible totreatment include airway hyper-responsiveness and occlusion that occurin conjunction with chronic asthma, smooth muscle cell proliferation inatherosclerosis, vascular occlusion following angioplasty, fibrosis andglomerular scarring as a result of renal disease, aortic stenosis,hypertrophy of synovial membranes in rheumatoid arthritis, andinflammation and scarring that occur with the progression of ulcerativecolitis, and Crohn's disease.

The Thorsett and Pleiss group has discovered a group of inhibitors ofVLA-4 which is described in Thorsett et al. “Substituted PhenylalanineType Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4,” WO99/06431 assigned to Athena Neurosciences, Inc. and American HomeProducts Corporation, which may be represented by general Formula(0.0.22):

where R¹, R², R³, R⁷, and Ar have substantially the same meaning asdescribed above with respect to WO 99/06390; and R⁵ is an optionallysubstituted member selected from the group consisting of —NHC(═O)R;alkoxyaryl; aryl; heteroaryl; —NRR′; alkoxy-NRR′; alkenyl; alkynyl;aryloxy; heteroaryloxy; alkoxy-heterocyclic; O-heterocyclic; tetrazolyl;—NRS(═O)₂-alkyl; alkenylsulfonylamino; alkynylsulfonylamino; alkoxy;amidine; —C(═O)NRR′; —NRC(═O)R′; —S(═O)₂-aryl; S(═O)₂-heteroaryl;—NRC(═O)NRR′; —NRC(═O)OR′; aminocarbonyl-(N-formylheterocyclyl); andalkyl-C(═O)NH-heterocyclyl.

A compound which illustrates the type of VLA-4 inhibitors disclosed isthat of Formula (0.0.23):

WO 99/06431 . . . Athena Neurosciences, Inc.

A related group of inhibitory compounds which has also been discoveredby the Thorsett and Pleiss group is described in Thorsett et al.,“Dipeptide and Related Compounds Which Inhibit Leukocyte AdhesionMediated by VLA-4,” WO 99/06432 assigned to Athena Neurosciences, Inc.and American Home Products Corporation. Inhibitory compounds of thistype are characterized by general Formula (0.0.24):

where R¹, R², R³, and R⁷ have substantially the same meaning asdescribed above with respect to WO 99/06390 and WO 99/06431; and R⁵ is-ALK-X or ═CH—Y where X and Y are defined to mean a wide variety ofgroups, all of which are optionally substituted.

An example of this type of VLA-4 inhibitor is the compound of Formula(0.0.25):

WO 99/06432 . . . Athena Neurosciences, Inc.

A further related group of VLA-4 inhibitory compounds which has alsobeen discovered by the Thorsett and Pleiss group is described in Dappenet al., “Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4,”WO 99/06433 assigned to Athena Neurosciences, Inc. and American HomeProducts Corporation. Inhibitory compounds of this type arecharacterized by general Formula (0.0.26):

where R¹, R², R³, and R⁷ have substantially the same meaning asdescribed above with respect to WO 99/06390, WO 99/06431, and WO99/06432; and X is —H; —OH; acylamino; —C(═O)OH; and optionallysubstituted alkyl; alkoxy; aryl; aryloxy; aryloxyaryl; carboxy-alkyl;carboxy-cycloalkyl; carboxy-aryl; carboxy-heteroaryl;carboxy-heterocyclic; and cycloalkyl.

The type of VLA-4 inhibitor described in the paragraph immediately abovemay be represented by the compound of Formula (0.0.27):

WO 99/06433 . . . Athena Neurosciences, Inc.

A still further group of VLA-4 inhibitory compounds which has beendiscovered by the Thorsett and Pleiss group is described in Ashwell etal., “4-Amino-Phenylalanine Type Compounds Which Inhibit LeukocyteAdhesion Mediated by VLA-4,” WO 99/06434 assigned to AthenaNeurosciences, Inc. and American Home Products Corporation. Inhibitorycompounds of this type are characterized by general Formula (0.0.28):

where R¹, R², R³, and R⁷ have substantially the same meaning asdescribed above with respect to WO 99/06390, WO 99/06431, WO 99/06432,and WO 99/06433; and R is —H, alkyl, or aryl; X is O, S, or NR; and Y isNRR′ or heterocycle, all of which are optionally substituted by a widevariety of groups.

This further type of VLA-4 inhibitor may be illustrated by the compoundof Formula (0.0.29):

WO 99/06434 . . . Athena Neurosciences, Inc.

Another group of VLA-4 inhibitors structurally related to those groupsof VLA-4 inhibitors described above, which has been discovered by theThorsett and Pleiss group is described in Thorsett et al., “DipeptideCompounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4,” WO99/06435 assigned to Athena Neurosciences, Inc. and American HomeProducts Corporation. Inhibitory compounds of this type arecharacterized by general Formula (0.0.30):

where R¹, R², R³, and R⁷ have substantially the same meaning asdescribed above with respect to WO 99/06390, WO 99/06431, WO 99/06432,WO 99/06433, and WO 99/06434; R⁵ has substantially the same meaning asdescribed above with respect to WO 99/06432; and R⁴ is —H; andoptionally substituted alkyl; cycloalkyl; aryl; heteroaryl;heterocyclic; and R¹ and R² may be taken together, or R² and R³ may betaken together, or R³ and R⁴ may be taken together to form cycloalkyl orheterocyclic groups.

This type of VLA-4 inhibitor may be illustrated by the compound ofFormula (0.0.31):

WO 99/06435 . . . Athena Neurosciences, Inc.

A still further group of structurally related inhibitors of VLA-4dependent cell adhesion which has been discovered by the Thorsett andPleiss group is described in Thorsett et al., “Benzyl Compounds WhichInhibit Leukocyte Adhesion Mediated by VLA-4,” WO 99/06436 assigned toAthena Neurosciences, Inc. and American Home Products Corporation.Inhibitory compounds of this type are characterized by general Formula(0.0.32):

where R¹, R², R³, and R⁷ have substantially the same meaning asdescribed above with respect to WO 99/06390, WO 99/06431, WO 99/06432,WO 99/06433, and WO 99/06434; and Ar is aryl or heteroaryl. This type ofVLA-4 inhibitor may be illustrated by the compound of Formula (0.0.33):

WO 99/06436 . . . Athena Neurosciences, Inc.

There is a further description of compounds related structurally tothose described above in WO 99/06390, WO 99/06431, WO 99/06432, WO99/06433, WO 99/06434, WO 99/06435, and WO 99/06436, but distinguishedfrom them by means of extensive provisos, that is set out in Thorsett etal., “Sulfonylated Dipeptide Compounds Which Inhibit Leukocyte AdhesionMediated by VLA-4,” WO 99/06437. Three such inhibitory compounds arethose of Formulas (0.0.34) through (0.0.36):

WO 99/06437 . . . Athena Neurosciences, Inc.

The Stilz and Wehner group has discovered a different class of compoundswhich possess inhibitory activity with regard to VLA-4 mediated celladhesion. These inhibitory compounds are described, e.g., in Stilz etal., “5-Ring Heterocycles As Inhibitors of Leukocyte Adhesion and AsVLA-4 Antagonists,” EP 842 943 assigned to Hoechst AG., which may becharacterized by general Formula (0.0.37):

where R is 4-amido-phenyl, 4-guanidino-phenyl, 4-aminomethyl-phenyl,3-amino-propyl, or 3-guanidino-propyl; R¹ is methyl or benzyl; R² is —H,methyl, ethyl, optionally substituted benzyl, or naphthylmethyl; R³ is amono-, di-, or tri-peptide; R⁴ is —H, methyl, or butyl; and R⁵ is —H,alkyl, cycloalkyl, or optionally substituted aryl. A representativecompound falling within the scope of the above-described class of VLA-4inhibitors is that of Formula (0.0.38):

EP 842 943 . . . Hoechst AG.

The Stilz and Wehner group has also discovered inhibitory compoundswhich are structurally close to those in above-described EP 842 943, andwhich are described in Stilz et al., “Heterocycles As Inhibitors ofLeukocyte Adhesion and As Antagonists of VLA-4,” EP 842 944. Thesecompounds may be characterized by general Formula (0.0.39):

where R⁴ is methyl or 4-R³-phenyl where R³ is 4,5-dihydroimidazol-2-ylor —C(═O)NH₂; R² is optionally substituted phenyl, pyridyl, or naphthyl;and R⁴ is —H, ethyl, n-butyl, or iso-butyl. A representative example ofthis type of inhibitory compound is that of Formula (0.0.40):

EP 842 944 . . . Hoechst AG.

Further inhibitory compounds structurally close to those inabove-described EP 842 944 are described in Stilz et al., EP 842 945,which may be characterized by general Formula (0.0.41):

where R is 4-R -phenyl where R² is —CN, —NO₂, optionally substituted—NH₂C(═O)NH, or —NH₂C(═O)NHCH₂; and R² is optionally substituted phenyl.A representative example of this type of inhibitory compound is that ofFormula (0.0.42):

EP 842 945 . . . Hoechst AG.

The Stilz and Wehner group has also further discovered inhibitors ofVLA-4 dependent cell adhesion which are described in Wehner et al.,“Imidazolidine Derivatives with VLA-4 Antagonist Activity Useful for theTreatment of Diseases Mediated by Leukocyte Adhesion,” EP 903 353assigned to Hoechst Marion Roussel Deutschland GmBH. Compounds of thistype are characterized by general Formula (0.0.43):

where A is optionally substituted alkylene, alkenylene, phenylene,-phenyl-alkylene, or alkylene-phenyl-; L and M are a bond or —CH₂—; X isoptionally substituted —CH(R⁷)— or —C(═CHR⁷)— where R⁷ is optionallysubstituted alkyl, phenyl, furyl, thienyl, pyrrolyl, indazolyl, orpyridinyl; R¹ is —H, cycloalkyl, optionally substituted alkyl, aryl,heterocyclyl; —C(═O)R⁶, or —SO₂R where R⁶ is —H, cycloalkyl, optionallysubstituted alkyl, aryl, or heterocyclyl; R² is —NH₂, —C(═O)NH₂, or—C(═O)OH; R³ is —H, alkyl, optionally substituted aryl, or heterocyclyl;and R⁵ is —C(═O)OH, tetrazolyl, —SO₃H, or —SO₂NH₂.

A typical VLA-4 inhibitor falling within the above-described class ofcompounds is illustrated by Formula (0.0.44):

EP 903 353 . . . Hoechst Marion Roussel Deutschland GmBH

Another group of inhibitory compounds closely related in structure tothose above-described has been discovered by the Stilz and Wehner groupand is described in Wehner et al., “Substituted Imidazoline Derivativeswith VLA-4 Antagonist Activity,” EP 918 059. Said group may beillustrated by general Formula (0.0.45):

where R is methyl or phenyl; R¹ is tert-butyl, propyl, iso-propyl,benzyl, cyclohexyl, or optionally substituted phenyl; R³ is adamantyl,—CH(CH₃)CH₂C(═O)OH, optionally substituted —CH(phenyl)CH₂C(═O)OH or—CH(phenyl)C(═O)OH; and R⁴ is —H or iso-butyl. An example of a compoundwhich illustrates this class of VLA-4 inhibitors is that of Formula(0.0.46):

EP 918 059 . . . Hoechst Marion Roussel Deutschland GmBH

Yet another class of VLA-4 inhibitors has been discovered by the Chengroup, e.g., as described in Chen et al., “Novel N-AroylphenylalanineDerivatives As Integrin Antagonists,” WO 99/10312 assigned to F.Hoffmann-La Roche AG. This class of inhibitors may be illustrated bygeneral Formulas (0.0.47) and (0.0.48):

where there are two sub-classes of compounds based on different A ringsas shown above. Further, the A and B rings may be replaced with variousheterocycles, although an ortho-substituted B ring is preferred. Arepresentative example of a compound falling within this class ofinhibitors is that of Formula (0.0.49):

WO 99/10312 . . . F. Hoffmann-La Roche AG.

A closely related group of inhibitors discovered by the Chen group isdescribed in Chen et al., WO 99/10313 assigned to F. Hoffmann-La RocheAG., which may be illustrated by general Formulas (0.0.50) and (0.0.51):

where there are two sub-classes of compounds as described above in thecase of those of Formulas (0.0.47) and (0.0.48). Further, the three Rgroups attached to the amide linker combine to form a quaternary center.A typical compound representative of the VLA-4 inhibitors in this classis that of Formula (0.0.52):

WO 99/10313 . . . F. Hoffmann-La Roche AG.

A still further class of inhibitors of VLA-4 dependent cell adhesion isthat discovered by Hagmann and his co-workers, e.g., as described inDurette and Hagmann, “Heterocyclic Amide Compounds As Cell AdhesionInhibitors,” WO 98/53814 which is assigned to Merck & Co., Inc. Thisclass of compounds may be illustrated by general Formula (0.0.53):

where X is —C(═O)OH or acid isostere; Y is —C(═O) or —S(═O)₂; R¹ throughR⁸ are selected from a wide variety of well known substituents; and A,B, and Z are selected so as to afford heterocycles of different typesand ring sizes. An example of an inhibitory compound which isrepresentative of this class is that of Formula (0.0.54):

WO 98/53814 . . . Merck & Co., Inc.

Another class of structurally related inhibitory compounds discovered bythe Hagmann group is described in Durette et al., “Biarylalkanoic AcidsAs Cell Adhesion Inhibitors,” WO 98/53817 assigned to Merck & Co., Inc.,which may be illustrated by general Formulas (0.0.55) and (0.0.56):

where X, Y, and R¹ through R⁷ have substantially the same meaning asdefined above for Formula (0.0.53), except that R² and R³ may be takentogether with the atoms to which they are attached to form a ring of 4to 7 members containing 0-2 additional heteroatoms selected from O, S,and N; and R^(b) is optionally substituted alkyl, alkenyl, alkynyl,arylalkyl, or heteroarylalkyl. A representative example of a compoundfalling within the scope of this class of VLA-4 inhibitors is that ofFormula (0.0.57):

WO 98/53817 . . . Merck & Co., Inc.

A further class of inhibitory compounds discovered by the Hagmann groupand closely related in structure to those described immediately above,is disclosed in Durette et al., “Sulfonamides As Cell AdhesionInhibitors,” WO 98/53818 assigned to Merck & Co., Inc. These compoundsmay be illustrated by general Formulas (0.0.57) and (0.0.58):

where R^(b) and R¹ through R⁷ have the same meaning as defined above forFormulas (0.0.55) and (0.0.56). A representative inhibitory compoundfalling within the above-described class is that of Formula (0.0.59):

WO 98/53818 . . . Merck & Co., Inc.

A still further class of VLA-4 inhibitory compounds related in structureto those described above has been discovered by the Hagmann group and isdisclosed in Delaszlo, “Azapeptide Acids As Cell Adhesion Inhibitors,”WO 99/20272. This class of inhibitors may be illustrated by generalFormula (0.0.60):

where m and n are 0 to 2; and X, Y, and R¹ through R⁶ have the samemeaning as defined above for Formulas (0.0.55) and (0.0.56).Representative inhibitory compounds falling within the above-describedclass are those of Formulas (0.0.61) and (0.0.62):

WO 99/20272 . . . Merck & Co., Inc.

Another class of VLA-4 dependent cell adhesion inhibitors discovered bythe Hagmann group is described in Delaszlo and Hagmann,“4-Substituted-4-Piperidine Carboxamide Derivatives Useful in theTreatment of Asthma, Inflammation and Multiple Sclerosis.” WO 99/25685assigned to Merck & Co., Inc. Compounds of this class may be illustratedby general Formula (0.0.63):

where X is a bond or substituted carbon atom; Z is —C(═O)OH or acidisostere; L is —C(═O)—, —S(═O)₂—; and R¹ through R⁵ have thesubstantially the same meaning as defined above for Formulas (0.0.55)and (0.0.56). A typical VLA-4 inhibitory compound in this class is thatof Formula (0.0.64):

WO 99/25685 . . . Merck & Co., Inc.

Another class of VLA-4 inhibitors closely related in structure to thosedescribed above is disclosed in Chang et al., “Cyclic Amino Acids AsCell Adhesion Inhibitors,” WO 99/26615 assigned to Merck & Co., Inc.Inhibitory compounds of this class are illustrated by general Formula(0.0.65):

where R indicates the ring size, and X, Y, and R¹ through R⁷ have thesame meaning as defined above for Formulas (0.0.55) and (0.0.56). Arepresentative example of an inhibitory compound within this class isthat of Formula (0.0.66):

WO 99/26615 . . . Merck & Co., Inc.

A class of VLA-4 dependent cell adhesion inhibitors has been discoveredwhich differs from those disclosed in WO 98/53814 described above onlywith respect to the terminal amino acid, which is a β-amino acid.Accordingly, reference may be made to general Formula (0.0.53) above.These β-amino acids are disclosed in Durette et al., “Substitutedβ-Alanine Derivatives As Cell Adhesion Inhibitors,” WO 99/26921 assignedto Merck & Co., Inc. Typical inhibitors of this type are illustrated inFormulas (0.0.67) and (0.0.68):

WO 99/26921 . . . Merck & Co., Inc.

A further class of VLA-4 dependent cell adhesion inhibitors related instructure to those described above has been discovered by the Hagmanngroup and is disclosed in Chang et al., “Substituted Pyrrole DerivatesAs Cell Adhesion Inhibitors,” WO 99/26922 assigned to Merck & Co., Inc.This class of inhibitors is illustrated by general Formula (0.0.69):

where Y and R¹ through R⁷ have the same meaning as defined above forFormulas (0.0.55) and (0.0.56), and X and Z have the same meaning asdefined above for Formula (0.0.63), except that the meanings arereversed because -X-Z- in (0.0.63) has been changed to -Z-X- in(0.0.69). An example of inhibitory compounds falling within this classis illustrated by Formula (0.0.70):

WO 99/26922 . . . Merck & Co., Inc.

Another class of VLA-4 inhibitory compounds discovered by the Hagmanngroup and closely related to those above is that described in Delaszloand Hagmann, “Para-Aminomethylaryl Carboxamide Derivatives,” WO 99/26923assigned to Merck & Co., Inc., and which may be represent by generalFormula (0.0.71):

where L, X, Z, and R¹ through R⁶ have substantially the same meaning asdefined above under Formulas (0.0.55) and (0.0.56). Ar is a 1,4substituted aryl or heteroaryl moiety. A typical compound falling withinthe scope of this class of VLA-4 inhibitors is illustrated as Formula(0.0.72):

WO 99/26923 . . . Merck & Co., Inc.

A different group has discovered a new class of VLA-4 antagonists whichis described in Wattanasin and Von Matt, “VLA-4 Antagonists,” WO99/37605 assigned to Novartis. The inhibitory compounds in this newclass may be represented by general Formula (0.0.73):

where Y is —C(═O)—, —S(═O)₂—, or —P(═O)₂—; Z is —(CH₂)_(n)—, —CHR—, or—NR—; W is —CH— or —N—; X is —C(═O)OH or acid isostere; and R¹ throughR⁴ are a wide variety of common substituents. A representative exampleof a VLA-4 inhibitor from this class is illustrated by Formula (0.0.74):

WO 99/37605 . . . Novartis

Another different group has discovered a further new class of compoundswhich inhibit VLA-4 dependent cell adhesion, which is described inAstles et al., “Substituted Anilides and Their Use in the Treatment ofVarious Disease States including Inflammation, arthritis, andatherosclerosis,” WO 99/23063 assigned to Rhone-Poulenc Rorer Ltd. Thisclass of VLA-4 inhibitors may be represented by general Formula(0.0.75):

where X¹, X², and X³ are —N— or —CR—; Ar¹ is aryl or heteroaryl; L² isan optionally substituted alkylene linkage; Y is carboxy, an acidbioisostere, or —C(═O)NRR; and R¹ is —H, halo, —OH, lower alkyl or loweralkoxy. A representative example of an inhibitory compound which fitsinto this class is illustrated by Formula (0.0.76):

WO 99/23063 . . . Rhone-Poulenc Rorer Ltd.

Another class of VLA-4 inhibitors which is closely related in structureto those described immediately above is described in Artles et al.“Biaryl β-Alanine Derivatives Useful As VLA-4 Antagonists,” WO 99/33789assigned to Rhone-Poulenc Rorer Ltd. Members of this class of inhibitorsmay be represented by general Formula (0.0.77):

where X¹, X², and Y have the same meaning as defined above under Formula(0.0.75). R⁴ is aryl or heteroaryl or is optionally substituted alkyl,alkenyl or alkynyl. A representative example of an inhibitory compoundwithin this class is illustrated by Formula (0.0.78):

WO 99/33789 . . . Rhone-Poulenc Rorer Ltd.

A further different group has also discovered a new class of VLA-4dependent cell adhesion inhibitors, which is described in Lobl et al.“Cyclic Peptide Inhibitors of β₁ and β₂ Integrin-Mediated Adhesion,” WO96/40781 assigned to Tanabe Seiyaku Co., Ltd. The inhibitors are cyclicpeptides which contain a free acid.

WO 96/40781 . . . Tanabe Seiyaku Co., Ltd.

Another class of VLA-4 inhibitors discovered by the same group isdescribed in Lobl et al. “Inhibitors of α₁β₄ Mediated Cell Adhesion,” WO98/58902 assigned to Tanabe Seiyaku Co., Ltd. and Pharmacia & UpjohnCompany. Members of this further class of VLA-4 inhibitors may berepresented by general Formula (0.0.79):

where R¹ is acid or amide; X is phenyl; and Z is amide or methyleneether. A representative example of an inhibitory compound from thisclass is that of Formula (0.0.80):

WO 98/58902 . . . Tanabe Seiyaku Co., Ltd.

Another class of VLA-4 inhibitors discovered by the same group isdescribed in Sircar et al. “Inhibitors of α4 Mediated Cell Adhesion,” WO99/36393 assigned to Tanabe Seiyaku Co., Ltd. Members of this class ofVLA-4 inhibitors may be characterized by general Formula (0.0.81):

where R¹ through R⁶, except R⁴, are selected from a wide variety ofcommon substituent groups; R⁴ is acid, acid isostere, or amide; A isaryl or heteroaryl; Q is a bond, —C(═O)—, or substituted alkylene; n is0 to 2; and W is —O—, —S—, —CH═CH—, or —N═CH—. A representative memberof this class of VLA-4 inhibitors is illustrated by Formula (0.0.82):

WO 99/36393 . . . Tanabe Seiyaku Co., Ltd.

A still further different group has also discovered a new class of VLA-4dependent cell adhesion inhibitors, which is described in Kogan et al.“Process to Inhibit Binding of the Integrin alpha 4 beta 1 to VCAM-1 orFibronectin,” WO 96/00581 assigned to Texas Biotechnology Corporation.This class of VLA-4 antagonists comprises cyclic peptides of from 5 to13 residues modeled after a portion of the CS1 peptide, that alsocontain a free acid.

WO 96/00581 . . . Texas Biotechnology Corporation

A yet still further different group has also discovered a new class ofVLA-4 antagonists, which is described in Dutta, “Fibronectin AdhesionInhibitors,” WO 96/20216 assigned to Zeneca Limited. This class of VLA-4antagonists comprises cyclic peptides that contain a free acid.

WO 96/00581 . . . Zeneca Limited

A related class of VLA-4 antagonists discovered by the same group isdescribed in Dutta, “Cyclic Tetrapeptide Dimers Useful As FibronectinInhibitors,” WO 97/02289 assigned to Zeneca Limited. This class of VLA-4antagonists comprises cyclic dimeric peptides in which a peptide 1 andpeptide 2 independently representing a tetrapeptide, are juxtaposed inparallel or antiparallel orientation by means of two linking moieties L1and L2.

WO 97/02289 . . . Zeneca Limited

Another related class of VLA-4 antagonists discovered by the same groupis described in Dutta, “Cyclic Octapeptide Derivatives That Are IntegrinAntagonists,” WO 97/49731 assigned to Zeneca Limited. This class ofVLA-4 antagonists comprises a variety of cyclic octapeptides containinga free acid.

WO 97/49731 . . . Zeneca Limited

The same group has also discovered a non-peptidal class of VLA-4antagonists which is described in Brittain and Johnstone, “ChemicalCompounds,” WO 99/24398 assigned to Zeneca Limited. Members of thisclass may be represented by general Formula (0.0.83):

where Y is —O—, —S—, or —S(═O)₂—; R¹ is urea; R¹¹ is acid or acidisostere; and m is 0 or 1 and when m is 0 then n is 1 to 4, and when mis 1 then n is 0. A representative member of this class of VLA-4antagonists is illustrated by Formula(0.0.84):

WO 99/24398 . . . Zeneca Limited

None of the references discussed above discloses or suggests thecompounds of the present invention.

Despite the above-described advances in the art with regard toinhibitors of VLA-4 mediated cell adhesion, the artisan will quicklyrecognize that the peptidyl inhibitors are prone to poor absorption,poor solubility and are subject to metabolism in vivo (both systemicallyand locally when administered directly into the lung) diminishing theiropportunity to appreciably affect the course of an inflammatory,respiratory or autoimmune disease.

Those of the above-described VLA-4 antagonists that are non-peptidal,i.e., that may be regarded as small molecules, are thereby able to avoidthe liabilities of peptidal agents as discussed above. However, thesmall molecule VLA-4 antagonists known in the art, as described indetail above, have not yet been established to possess sufficiently highlevels of the desired potency with low levels of acceptable sideeffects, together with adequately workable pharmacokinetic andadsorption profiles, such as would enable such compounds to becomesuitable therapeutic agents for use in treating the diseases andconditions discussed herein. Accordingly, there still exists in the arta need for non-peptidyl or semi-peptidyl therapeutic agents which caneffectively treat or prevent such pathological conditions.

SUMMARY OF THE INVENTION

The present invention is concerned with compositions which inhibit VLA-4dependent cell adhesion in a mammal. The present invention thus relatesto a compound of Formula (1.0.0):

and pharmaceutically acceptable salts and other prodrug derivativesthereof, wherein:

A is (C₁-C₆) alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl asdefined herein; where said alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl is optionally substituted with 0 to 3 R⁹; or is a memberselected from the group consisiting of the following radicals:A¹-NHC(═O)NH-A²-, A¹-NHC(═O)O-A²-, A¹-OC(═O)NH-A²-, A¹-NHSO₂NH-A²-,A¹-NHC(═O)-A²-, A¹-C(═O)NH-A²-, A¹-NHSO₂-A²-, A¹-SO₂NH-A²-,A¹-(CH₂)_(r)O-A²-, A¹-O(CH₂)_(r)-A²-, A¹-(CH₂)_(r)-A²-, where A¹ and A²are each independently selected from the group consisting of hydrogen,aryl, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl,heteroaryl, and heterocyclyl; where said aryl, alkyl, cycloalkyl,heteroaryl, or heterocyclyl group is substituted with 0 to 3 R⁹;

B is a member independently selected from the group consisting of thefollowing:

 where the symbol “*” indicates the point of attachment of the moietyrepresented by each partial Formula (1.1.0) through (1.1.22) to themoiety “CR²R³” in Formula (1.0.0); and

the symbol “Π” indicates the point of attachment of the moietyrepresented by each partial Formula (1.1.0) through (1.1.22) to themoiety “E” in Formula (1.0.0); Each of Formula (1.1.0) through (1.1.22),with the exception of formulas (1.1.10) and (1.1.22), may be optionallysubstituted with R⁹;

E is a single bond; —O—; —NR¹⁰—; —CH═CH—; —CC—; —S(═O)_(q);—CR¹¹R¹²NR¹⁰—; or —CR¹¹R¹²—;

X is —O—; —C(═O)—; —(═O)_(q); or —NR¹⁰—;

X¹, X² and X³ are each independently selected from the group consistingof CH, CR⁹ or N;

Y is a single bond; —C(═O)—; —C(═S)—; or —S(═O)₂—;

k is an integer independently selected from 0, 1 and 2;

m is an integer independently selected from 0 and 1;

n is an integer independently selected from 0, land 2;

p is an integer independently selected from 0 and 1, provided that pmust be selected as 1 where B is selected as partial formula (1.1.0)through (1.1.11);

q is an integer independently selected from 0,1 and 2;

r is an integer independently selected from 0, 1 and 2;

R² and R³ are each independently selected from the group consisting ofhydrogen; (C₁-C₆) alkyl substituted with 0 to 3 R¹³; (C₂-C₆) alkenylsubstituted with 0 to 3 R¹³; (C₃-C₁₄) carbocyclic ring systemsubstituted with 0 to 3 R¹³; a heterocyclyl ring as defined herein,substituted with 0 to 3 R¹³; (C₁-C₆) alkyl-OR⁵ substituted with 0 to 3R¹³; C₁-C₆) alkyl-SR⁵ substituted with 0 to 3 R¹³; (C₁-C₆) alkyl-SO₂R⁵substituted with 0 to 3 R¹³; a heteroaryl ring as defined herein,substituted with 0 to 3 R¹³; an aryl ring as defined herein, substitutedwith 0 to 3 R¹³;

 provided that

 R² and R³ are each defined as above; or they are taken together asdefined below; or one of them is taken together with R⁴ as definedbelow, in which case the other has the meaning of hydrogen or methyl;

R² and R³ are taken together to form either a cycloalkyl or heterocyclylring substituted with 0 to 3 R¹³; or

R² or R³ is taken together with R⁴ and the carbon and nitrogen atoms towhich they are respectively attached to form a heteroaryl orheterocyclyl group as defined herein, substituted with 0 to 3 R¹³;

R⁴ is hydrogen; or (C₁-C₆) alkyl optionally substituted with R¹³; or R⁴may be taken together with either R² or R³ to form a carbocyclic orheterocyclic ring;

R⁵ and R⁶ are independently hydrogen; (C₁-C₆) alkyl; (C₂-C₆) alkenyl;(C₂-C₆) alkynyl; CF₃; aryl; cycloalkyl; heteroaryl; or heterocyclyl;

R⁷ is (C₁-C₆) alkyl; (CH₂)_(k)OR⁵; (CH₂)_(k)NR⁶C(═O)R⁵;(CH₂)_(k)NR⁶C(═O)OR⁵; (CH₂)_(k)NR⁶SO₂R⁵; (CH₂)_(k)NR⁶R⁵; F; CF₃; OCF₃;aryl, substituted with 0 to 3 R⁹; heterocyclyl, substituted with 0 to 3R⁹; heteroaryl, substituted with 0 to 3 R⁹; cycloalkyl, substituted with0 to 3 R⁹; or R⁷ may be taken together with R⁸ to form a cycloalkyl orheterocyclyl ring; or R⁷ may be taken together with R¹¹ to form acycloalkyl or heterocyclyl ring;

R⁸ is hydrogen; F; (C₁-C₆) alkyl or (C₁-C₆) alkoxy;

R⁹ is halogen; (C₁-C₆) alkyl; C₁-C₆) alkoxy; (C₃-C₆) cycloalkyl; (C₃-C₆)cycloalkoxy; cyano; (CH₂)_(k)OH; C(═O)R⁵; (CH₂)_(k)C(O)NR⁵R⁶;(CH₂)_(k)NR⁵R⁶; (CH₂)_(k)NR⁵SO₂R⁶; CF₃; OCF₃; SO₂NR⁵R⁶;(CH₂)_(m)C(═O)OR⁵; when R⁹ is attached to a saturated carbon atom R⁹ maybe ═O or ═S; when R⁹ is attached to a sulphur atom R⁹ may be ═O;

R¹⁰ is hydrogen; C(═O)R⁵; C(═O)OR⁵; (C₁-C₆) alkyl; aryl; heterocyclyl;heteroaryl; cycloalkyl; or SO₂R⁵;

R¹¹ and R¹² are independently hydrogen; (C₁-C₆) alkyl; hydroxy; cyano;(C₁-C₆) alkoxy; NR⁶C(═O)R⁵; NR⁶SO₂R⁵; NR⁶R⁵; CF₃; F; aryl; heterocyclyl;heteroaryl; cycloalkyl; cycloalkoxy; or R¹¹ may be taken together withR¹² to form a cycloalkyl or heterocyclyl ring;

R¹³ is independently selected from the group consisting of halogen; CF₃;(C₁-C₆) alkyl; aryl; heteroaryl; heterocyclyl; hydroxy; cyano; (C₁-C₆)alkoxy; (C₃-C₆) cycloalkyl; (C₃-C₆) cycloalkoxy; (C₂-C₆) alkynyl;(C₂-C₆) alkenyl; —NR⁶R⁵; —C(═O)NR⁵R⁶; SO₂R⁵; C(═O)R⁵; NR⁵SO₂R⁶;NR⁵C(═O)R⁶; C(═O)NR⁵SO₂R⁶; NR⁵C(═O)OR⁶; and SO₂NR⁶R⁵.

The present invention is also concerned with pharmaceutical compositionscomprising one or more of the compounds of the present invention asdescribed above together with a pharmaceutically acceptable carrier forsaid compound(s), wherein the amount of said compound(s) present iseffective for preventing, inhibiting, suppressing or reducing celladhesion and consequent or associated pathogenic processes subsequentlymediated by VLA-4. The present invention is further concerned withpharmaceutical compositions which in addition to containing a compoundof the present invention, additionally comprise one or more therapeuticagents selected from the group consisting essentially ofanti-inflammatory corticosteroids, nonsteroidal anti-inflammatoryagents, bronchodilators, anti-asthmatic agents, and immunosuppressantagents.

The present invention is still further concerned with a method oftreating or preventing an inflammatory, autoimmune or respiratorydiseases by inhibiting cell adhesion and consequent or associatedpathogenic processes subsequently mediated by VLA-4, comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a pharmaceutical composition of the presentinvention. The pharmaceutical compositions of the present invention maybe used in the treatment of many inflammatory, autoimmune andrespiratory diseases, including but not limited to asthma, multiplesclerosis, rheumatoid arthritis, osteoarthritis, inflammatory boweldisease, psoriasis, host rejection following organ transplantation,atherosclerosis, and other diseases mediated by or associated withVLA-4.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds which inhibit cell adhesionand subsequent pathogenic processes mediated by VLA-4. These compounds,which are thus useful in the treatment of many inflammatory, autoimmuneamd respiratory diseases, may be illustrated by Formula (1.0.0):

For compounds of Formula (1.0.0), the terminal group identified as A hasthe meaning alkyl, cycloalkyl, aryl, heteroaryl or heterocyclylsubstituted with 0 to 3 R⁹; or is a member selected from the groupconsisiting of the following radicals: A¹-NHC(═O)NH-A²-,A¹-NHC(═O)O-A²-, A¹-OC(═O)NH-A²-, A¹-NHSO₂NH-A²-, A¹-NHC(═O)-A²-,A¹-C(═O)NH-A²-, A¹-NHSO₂-A²-, A¹-SO₂NH-A²-, A¹-(CH₂)_(r)O-A²-,A¹O(CH₂)_(r)-A²-, A¹(CH₂)_(r)-A²-, where A¹ and A² is each independentlyselected from the group consisting of hydrogen, aryl, alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, and heterocyclyl; where said aryl,alkyl, alkenyl, cycloalkyl, heteroaryl, or heterocyclyl group issubstituted with 0 to 3 R⁹.

The term “alkyl” as used with reference to “A”, as well as in othercontexts throughout the instant specification, and whether used alone orin combination, refers to a straight-chain or branched chain alkylradical containing the indicated number of carbon atoms, usually from 1to 6 but often from 1 to 4, carbon atoms. Examples of such radicalsinclude, but are not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-amyl, and hexyl.

The term “cycloalkyl” as used with reference to “A”, as well as in othercontexts throughout the instant specification, and whether used alone orin combination, refers to a cyclic alkyl radical containing from 3 to 6carbon atoms. Examples of such cycloalkyl radicals include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “aryl” as used with reference to “A”, as well as in othercontexts throughout the instant specification, is intended to refer to acarbocyclic aromatic group which is a member selected from the groupconsisting essentially of phenyl, naphthyl, indenyl, indanyl, andfluorenyl. It is preferred, however, that where “A” is “aryl”, that itis phenyl.

The term “heteroaryl” as used with reference to “A”, as well as in othercontexts throughout the instant specification, is intended to refer to aheterocyclic aromatic group which is a member selected from the groupconsisting essentially of furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazolinyl,pyrazolyl, pyrazolinyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl,pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyranyl, parathiazinyl,indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl,2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and pyrazolo[1,5-c]triazinyl.

It is preferred, however, that where “A” is “heteroaryl” that it isfuryl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl,pyridyl, pyrimidinyl, indolyl, benzo[b]furanyl, benzimidazolyl, orquinolinyl. More preferably, “A” is pyridyl.

The terms “heterocylic” and “heterocyclyl” as used with reference to“A”, as well as in other contexts throughout the instant specification,are both intended to refer to a non-aromatic 3- to 10-memberedcarbocyclic ring in which at least one of the carbon atoms of the ringhas been replaced by a heteroatom selected from N, O or S. Preferablytwo, and more preferably one heteroatom is present, except that in thecase of nitrogen, as many as four N heteroatoms may be present. Theheterocyclyl group may comprise one or two fused rings, and further mayinclude an aryl-fused ring. In a preferred meaning, “heterocyclyl”refers to a member selected from the group consisting essentially ofoxiranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrazolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, andbenzodioxolane, especially 1,3-benzodioxol-5-yl.

It is preferred, however, that where “A” is “heterocyclyl” that it ispyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

Where “A” is defined as a moiety selected from the above-defined alkyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl groups, said moiety may besubstituted with 0 to 3 R⁹. The choice of “0” merely denotes that thereare no substituents, substitution being optional. Where substitutionoccurs, preferably there are two substituents, and more preferably thereis only one substituent.

Where a substituent R⁹ is used, it will be independently selected fromthe group consisting essentially of halogen; (C₁-C₆) alkyl; C₁-C₆)alkoxy; (C₃-C₆) cycloalkyl; (C₃-C₆) cycloalkoxy; cyano; hydroxy;C(═O)R⁵; C(O)NR⁵R⁶; NR⁵R⁶; NR⁵SO₂R⁶; CF₃; OCF₃; SO₂NR⁵R⁶; C(═O)OR⁵; whenR₉ is attached to a saturated carbon atom R⁹ may be ═O or ═S; when R⁹ isattached to a sulphur atom R⁹ may be ═O; where R⁵ and R⁶ are as furtherdefined herein. Preferably, however, there is a single substituent andit is F, Cl, OH, methyl, methoxy, cyclohexyl, acetyl, cyclopropyloxy, orF₃C—.

The term “alkoxy” as used with reference to the substituents “R⁹” on thegroup “A”, as well as in other contexts throughout the instantspecification, and whether used alone or in combination, refers to analkyl ether radical, wherein the term “alkyl” is as defined above.Examples of suitable alkyl ether radicals include, but are not limitedto, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,sec-butoxy, and tert-butoxy.

The term “cycloalkoxy” as used with reference to the substituents “R⁹”on the group “A”, as well as in other contexts throughout the instantspecification, and whether used alone or in combination, refers to ancycloalkyl ether radical, wherein the term “cycloalkyl” is as definedabove. Examples of suitable cycloalkoxy radicals include, but are notlimited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, andcyclohexyloxy.

A preferred meaning of “A” is that of a divalent radical which is amember selected from the group consisting of the following radicals:A1-NHC(═O)NH-A2-, A1-NHC(═O)O-A2-, A1-OC(═O)NH-A2-, A1-NHSO2NH-A2-,A1-NHC(═O)-A2-, A1-C(═O)NH-A2-, A1-NHSO2-A2-, A1-SO2NH-A2-,A1-(CH2)_(r)O-A2-, A1-O (CH2)_(r)-A2-, A1-(CH2)_(r)-A2-,A1-(CH₂)_(r)-A2-, where A¹ and A² is each independently selected fromthe group consisting of hydrogen, aryl, (C₁-C₆) alkyl, cycloalkyl,heteroaryl, and heterocyclyl; where said aryl, alkyl, cycloalkyl,heteroaryl, or heterocyclyl group is substituted with 0 to 3 R⁹. Thealkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group which isbonded to one or both sides of the ureido radical is selected inaccordance with the definitions set out above, as are the 0 to 3substituents R⁹. It is preferred that an aryl group be covalently bondedto the both sides of the ureido radical, and it is further preferredthat this aryl group be phenyl. It is most preferred that said phenylgroup have a single substituent which is preferably F, Cl, methyl,methoxy, or F₃C—. Examples of the preferred meanings of “A” are shown inpartial Formulas (4.0.0) though (4.0.11):

The component of the compounds of Formula (1.0.0) which is immediatelyadjacent to the “A” component, is a single bond, or a methylene orethylene bridging element where n=0, 1 or 2, respectively. It ispreferred that n=1 and that there be a methylene bridge. Accordingly,within the context of the above-stated preferences for the meaning ofthe “A” component, and adding the methylene bridge, the following mostpreferred termini which include the component “A”, may be represented bythe following partial Formulas (4.1.0) through (4.1.23):

It will be further noted partial structural formulas that the preferredmethylene bridge is also preferably attached to the N,N′-diphenylureidogroup in a para relationship to the point of attachment of the divalentureido group to the phenyl group involved.

The “Y” component of Formula (1.0.0) may be —C(═O)—; —C(═S)—; or—S(═O)₂—. Overall, however, it is most preferred that “Y” be a carbonylmoiety, i.e., that “Y” is the moiety —C(═O)—.

The next component of the compounds of Formula (1.0.0) is —NR⁴CR²R³—. Inthis component R² and R³ are each independently selected from the groupconsisting of hydrogen; (C₁-C₆) alkyl substituted with 0 to 3 R¹³;(C₂-C₆) alkenyl substituted with 0 to 3 R¹³; a (C₃-C₁₄) carbocyclic ringsystem substituted with 0 to 3 R¹³; a heterocyclyl ring as definedherein, substituted with 0 to 3 R¹³; (C₁-C₆) alkyl-OR⁵ substituted with0 to 3 R¹³; (c₁-C₆) alkyl-SR⁵ substituted with 0 to 3 R¹³; (C₁-C₆)alkyl-SO₂R⁵ substituted with 0 to 3 R¹³; a heteroaryl ring as definedherein, substituted with 0 to 3 R¹³; and an aryl ring as defined herein,substituted with 0 to 3 R¹³. R² and R³ may also be taken together inaccordance with an optional definition of R² and R³, in which case theyform a cycloalkyl or heterocyclyl ring substituted with 0 to 3 R³. Forexample, where R² and R³ are taken together to form a spirocycliccyclopropyl, cyclobutyl, or cyclopentyl group, the resulting compoundsof the present invention will include moieties such as those of partialFormulas (1.2.0) through (1.2.2):

Another preferred sub-group of compounds of the present invention isthat formed when either R² or R³ is taken together with R⁴ and thecarbon and nitrogen atoms to which they are respectively attached toform a heteroaryl or heterocyclyl group as defined herein. Saidheteroaryl or heterocyclycl group may, in turn, be substituted with 0 to3 R¹³. In accordance with the above-mentioned proviso, when either R² orR³ is taken together with R⁴, the other must be hydrogen or methyl. Thesub-group may be represented by partial Formula (1.3.0) as follows:

where the symbol “*” indicates the point of attachment of the moietyrepresented by partial Formula (1.3.0) to the moiety “Y” in Formula(1.0.0); and the symbol “Π” indicates the point of attachment of themoiety represented by partial Formula (1.3.0) to “B” in Formula (1.0.0),defined by partial Formulas (1.1.0) through (1.1.22). The substituent“R^(⅔)” indicates the presence of either the R² substituent or the R³substituent. They both may not be present, since one or the other hasalready been selected to be taken together with R⁴ to form theheteroaryl or heterocyclyl group of partial Formula (1.3.0), representedas follows:

It will be understood that whether R² or R³ is present, it will have themeaning of hydrogen, alkyl or methyl.

Accordingly, this sub-group of the group “—NR⁴CR²R³B—” represented bypartial Formula (1.3.0) includes, but is not limited to, the embodimentswhich are represented by partial Formulas (1.3.1) through (1.3.20):

where the symbol “*” indicates the point of attachment of the moietyrepresented by each partial Formula (1.3.1) through (1.3.20) to themoiety “Y” in Formula (1.0.0); and the symbol “Π” indicates the point ofattachment of the moiety represented by each partial Formula (1.3.1)through (1.3.20) to the moiety “E” in Formula (1.0.0).

With reference to the optional substituent R¹³ which may be present onthe R² and R³ substituents of the B component, R¹³ is absent when “0” isselected. It is preferred that R¹³ either be absent or be present as asingle substituent selected from halogen; CF₃; (C₁-C₆) alkyl; aryl;heteroaryl; heterocyclyl; hydroxy; cyano; (C₁-C₆) alkoxy; (C₃-C₁₄)carbocyclic ring system; (C₃-C₆) cycloalkoxy; (C₂-C₆) alkynyl; (C₂-C₆)alkenyl; —NR⁶R⁵; —C(═O)NR⁵R⁶; SO₂R⁵; C(═O)R⁵; NR⁵SO₂R⁶; NR⁵C(═O)R⁶;C(═O)NR⁵SO₂R⁶; NR⁵C(═O)OR⁶; and SO₂NR⁵. With reference to the optionalsubstituent R¹³, but also with reference to the remainder of the instantspecification, the term “alkynyl” alone or in combination, refers to astraight-chain or branched-chain alkynyl radical containing from 2 to 6,preferably 2 to 4 carbon atoms. Examples of such radicals include, butare not limited to, ethynyl (acetylenyl), propynyl, propargyl, butynyl,hexynyl, decynyl and the like.

With reference to the definition of R¹³, the term “alkenyl” alone or incombination, refers to a straight-chain or branched-chain alkenylradical containing from 2 to 6, preferably 2 to 4 carbon atoms. Examplesof such radicals include, but are not limited to, ethenyl, E- andZ-propenyl, iso-propenyl, E- and Z-butenyl, E- and Z-iso-butenyl, and E-and Z-pentenyl.

The term “(C₃-C₁₄)carbocyclic ring system” as used with reference to R²and R³, as well as in other contexts throughout the instantspecification, used alone or in combination, is intended to refer tocycloalkyl and cycloalkenyl groups consisting of one, two or three fusedrings containing a total of from three to fourteen carbon atoms. Theterm “cycloalkyl” in turn, means a cyclic alkyl radical containing from3 to 8, preferably from 3 to 6, carbon atoms. Examples of suchcycloalkyl radicals include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like. The term“cycloalkenyl” on the other hand, refers to a cyclic carbocyclecontaining from 4 to 8, preferably 5 or 6, carbon atoms and one or moredouble bonds. Examples of such cycloalkenyl radicals include, but arenot limited to, cyclopentenyl, cyclohexenyl, and cyclopentadienyl.

Where two or three fused rings are present, one of the rings may be acycloalkyl ring system while the other one or two rings may becycloalkenyl ring systems.

It is preferred that when one of R² and R³ is hydrogen that the other beselected from the group consisting essentially of hydrogen, methyl,ethyl, propyl, butyl, and iso-butyl; hydroxymethyl, methoxymethyl;allyl, propenyl, E- and Z-iso-butenyl, and E- and Z-pentenyl;cyclopropylmethyl, cyclopentylmethyl and cyclohexylmethyl;cyclohexenylmethyl, benzyl, benzyloxymethyl and phenoxymethyl;2-(methylthio)ethyl; 3-(hydroxypropylthio)methyl;2-(methylsulfonyl)ethyl; 4-(acetylamino)butyl;4-(methylsulfonylamino)butyl; and 4-ethoxycarbonylamino)butyl.

The next component, the “B” group of the compounds of Formula (1.0.0) isone of the more important portions of the molecule and is a key elementin providing the unexpectedly good biological properties possessed bythe compounds of the present invention. The “B” group comprises a memberselected from the group consisting of partial Formulas (1.1.0) through(1.1.22):

where the symbol “*” indicates the point of attachment of the moietyrepresented by each partial Formula (1.1.0) through (1.1.22) to themoiety “CR²R³” in Formula (1.0.0); and the symbol “Π” indicates thepoint of attachment of the moiety represented by each partial Formula(1.1.0) through (1.1.22) to the moiety “E” in Formula (1.0.0).

All of the above partial Formulas (1.1.0) through (1.1.22) inclusive areillustrated as fragments in the manner above-described, wherein thepoints of attachment at either end of a particular fragment areindicated by the symbols “*” and “Π”.

In the above partial formulas defining the B component of the compoundsof Formula (1.0.0), the moiety “X” may be oxygen; sulfur (q=0) andsulfur to which two oxygen atoms is attached (q=2), i.e., sulfonyl; orNH (R¹⁰=hydrogen) or nitrogen which is substituted (R¹⁰=(C₁-C₆)alkyl;(C₃-C₆)cycloalkyl; heterocyclyl; heteroaryl; or aryl). It is preferred,however, that “X” be simply oxygen, sulfur or NH.

Attached to component B in the compounds of Formula (1.0.0) are theremaining structural elements which may be represented by partialFormula (1.4.0):

It will be noted first that the moiety represented by partial Formula(1.4.0) is directly attached to component B in the overall compound ofFormula (1.0.0). E is a single bond; oxygen; —NR¹⁰—; —CH═CH—; or—CR¹¹R¹²—.

Where a substituent R¹⁰ is used, it will be independently selected fromthe group consisting essentially of hydrogen, C(═O)R⁵; (C₁-C₆) alkyl;aryl; heterocyclyl; heteroaryl; cycloalkyl; or SO₂R⁵.

Where substituents R¹¹ and R¹² are used, they will be independentlyselected from the group consisting essentially of hydrogen; (C₁-C₆)alkyl; hydroxy; (C₁-C₆) alkoxy; NR⁶COR⁵; NR⁶SO₂R⁵; NR⁶R⁵; CF₃; F; aryl;heterocyclyl; heteroaryl; cycloalkyl; and cycloalkoxy. R¹¹ may be takentogether with R¹² to form a cycloalkyl or heterocyclyl ring. R⁵ and R⁶are independently hydrogen; (C₁-C₆) alkyl; CF₃; aryl; cycloalkyl;heteroaryl; or heterocyclyl.

The groups (C₁-C₆)alkyl, (C₁-C₆)alkoxy, aryl, heterocyclyl, heteroaryl,cycloalkyl and cycloalkoxy have already been defined in detail above.Within the meaning of these groups it is preferred that R¹¹ and R¹² beindependently selected from the group consisting of methyl, ethyl,propyl, butyl, iso-butyl, methoxy, cyclopropoxy, cyclopropyl, phenyl,morpholinyl, piperidinyl and pyridyl.

In the portions of the compounds of the present invention represented bypartial Formula (1.4.0) above, the moiety E is followed by an optionalmethylene bridge: (—CH₂—)_(m) where m is an integer independentlyselected from 0 and 1.

The next component of Formula (1.0.0) is represented by “—(CR⁷R⁸)_(p)—”in which “p” is selected from the integers 0 and 1, provided that “p”must be selected as 1 where “B” is selected as partial formula (1.1.0)through (1.1.11).

The substituent R⁷ is selected from the group consisting of (C₁-C₆)alkyl; hydroxy; (C₁-C₆) alkoxy; NHC(═O)R⁵; NHSO₂R⁵; NR⁶R⁵; F; CF₃; OCF₃;aryl; heterocyclyl; heteroaryl; cycloalkyl; or R⁷ may be taken togetherwith R⁸ to form a cycloalkyl or heterocyclyl ring. The substituent R⁸ isselected from hydrogen; F; (C₁-C₆) alkyl or (C₁-C₆) alkoxy.

The final component of Formula (1.0.0) is the “—C(═O)OR¹” group whereinR¹ is hydrogen.

The compontent represented by partial Formula (1.4.0) includes, but isnot limited to, the embodiments which are represented by partialFormulas (1.4.1) through (1.4.20):

Included within the scope of the present invention are thepharmaceutically acceptable derivatives of the compounds of Formula(1.0.0). The expression “pharmaceutically acceptable derivative” as usedin the instant specification denotes any pharmaceutically acceptablesalt of a compound of Formula (1.0.0). Further included within the scopeof the present invention is any other compound which, uponadministration to a patient, is capable of directly or indirectlyproviding a compound of Formula (1.0.0). Such compounds are recognizedas prodrugs, and a number of established procedures are available forpreparing such prodrug forms of the compounds of Formula (1.0.0).

The term “patient” as used above and throughout the instantspecification, refers to mammals, including humans. And where the term“cell” is used it refers to mammalian cells, including human cells,unless otherwise specified.

Further included within the scope of the present invention aremetabolites or residues of the compounds of Formula (1.0.0) whichpossess biological activity such that they are able to inhibit celladhesion and consequent or associated pathogenic processes subsequentlymediated by VLA-4. Once synthesized, the inhibitory activities and VLA-4specificities of the compounds of Formula (1.0.0) according to thisinvention may be determined using in vitro and in vivo assays which aredescribed in detail further below.

The desirable biological activity of the compounds of Formula (1.0.0)may also be improved by appending thereto appropriate functionalitieswhich will function to enhance existing biological properties of thecompound, improve the selectivity of the compound for the existingbiological activities, or add to the existing biological activitiesfurther desirable biological activities. Such modifications are known inthe art and include those which increase biological penetration into agiven biological system, e.g., blood, the lymphatic system, and centralnervous system; increase oral availability; increase solubility to allowadministration by injection; alter metabolism; and alter the rate ofexcretion of the compound of Formula (1.0.0).

In view of the above definitions and others throughout the instantspecification, other chemical and biological terms used herein can beeasily understood by those of skill in the art. The defined terms may beused alone or in any combination thereof. The preferred and morepreferred chain lengths of the radicals which have been specified hereinapply to all such combinations.

Further pursuant to the descriptions above of certain preferredsubgeneric and more preferred subgeneric definitions of the compounds ofFormula (1.0.0), there follows an enumeration of preferred and morepreferred species in order to provide a further illustration of thepresent invention.

Compounds which include the moiety of partial Formula (1.1.0):

3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-5-yl]-2-methyl-propionicacid

2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-5-yl]-propionicacid

2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-5-yl]-propionicacid

2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-4,5-dihydro-oxazol-5-yl}-propionicacid

2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-5-yl]-propionicacid

2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-5-yl}-propionicacid

2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-oxazol-5-yl)-propionicacid

2-Methyl-3-[2-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-5-yl]-propionicacid

2-Formylamino-3-{2-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-4,5-dihydro-thiazol-5-yl}-propionicacid

2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-oxazol-5-yl)-propionicacid

2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-oxazol-5-yl)-propionicacid

2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-5-yl]-propionicacid

2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-5-yl]-propionicacid

2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-4,5-dihydro-oxazol-5-yl}-propionicacid

2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-thiazol-5-yl}-propionicacid

3-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-3H-imidazol-4-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-5-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.1):

3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-4-yl]-2-methyl-propionicacid

2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methylbutyl)-4,5-dihydro-oxazol-4-yl]-propionicacid

2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-4-yl]-propionicacid

2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-4,5-dihydro-oxazol-4-yl}-propionicacid

2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-4-yl]-propionicacid

2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-4-yl}-propionicacid

2-(Butane-1-sulfonylamino)3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-oxazol-4-yl)-propionicacid

2-Methyl-3-[2-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydrooxazol-4-yl]-propionicacid

2-Acetylamino-3-{2-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-4,5-dihydro-thiazol-4-yl}-propionicacid

2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-oxazol-4-yl)-propionicacid

2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-oxazol-4-yl)-propionicacid

2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-4-yl]-propionicacid

2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-4-yl]-propionicacid

2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-4,5-dihydro-oxazol-4-yl}-propionicacid

2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-thiazol-4-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-4-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.2):

3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-5-yl]-2-methyl-propionicacid

2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-5-yl]-propionicacid

2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-5-yl]-propionicacid

2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-oxazol-5-yl}-propionicacid

2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionicacid

2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-5-yl}-propionicacid

2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-5-yl)-propionicacid

2-Methyl-3-[2-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionicacid

2-Acetylamino-3-{2-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiazol-5-yl}-propionicacid

2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-5-yl)-propionicacid

2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-5-yl)-propionicacid

2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionicacid

2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionicacid

2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-oxazol-5-yl}-propionicacid

2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-thiazol-5-yl}-propionicacid

3-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-3H-imidazol-4-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-5-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.3):

3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-4-yl]-2-methyl-propionicacid

2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-4-yl]-propionic acid

2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-4-yl]-propionicacid

2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-oxazol-4-yl}-propionic acid

2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-4-yl]-propionicacid

2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-4-yl}-propionicacid

2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-4-yl)-propionicacid

2-Methyl-3-[2-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-4-yl]-propionicacid

2-Formylamino-3-{2-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiazol-4-yl}-propionicacid

2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-4-yl)-propionicacid

2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-4-yl)-propionicacid

2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-4-yl]-propionicacid

2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-4-yl]-propionicacid

2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-oxazol-4-yl}-propionicacid

2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-thiazol-4-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-4-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.4):

3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-isooxazol-5-yl]-2-methyl-propionicacid

2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-isoxazol-5-yl]-propionicacid

2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-isoxazol-5-yl]-propionicacid

2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-4,5-dihydro-isoxazol-5-yl}-propionicacid

2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydroisoxazol-5-yl]-propionicacid

2-Allyloxycarbonylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methylamino)-methyl]-4,5-dihydro-isoxazol-5-yl}-propionicacid

2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-isoxazol-5-yl)-propionicacid

2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydroisoxazol-5-yl]-propionicacid

2-Formylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-4,5-dihydro-isothiazol-5-yl}-propionicacid

2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-isoxazol-5-yl)-propionicacid

2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-isoxazol-5-yl)-propionicacid

2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-isoxazol-5-yl]-propionicacid

2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-isoxazol-5-yl]-propionicacid

2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-4,5-dihydro-isoxazol-5-yl}-propionicacid

2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-isothiazol-5-yl}-propionicacid

3-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-3,4-dihydro-2H-pyrazol-3-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-isoxazol-5-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.5):

3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-pyrazol-1-yl]-2-methyl-propionicacid

2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-pyrazol-1-yl]-propionicacid

2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-pyrazol-1-yl]-propionicacid

2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl-amino)-ethyl]-4,5-dihydro-pyrazol-1-yl}-propionicacid

2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionicacid

2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-pyrazol-1-yl)-propionicacid

2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionicacid

2-Acetylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-4,5-dihydro-pyrazol-1-yl}-propionicacid

2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-pyrazol-1-yl)-propionicacid

2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-pyrazol-1-yl)-propionicacid

2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionicacid

2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionicacid

2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-4,5-dihydro-pyrazol-1-yl}-propionicacid

2-Formylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-pyrazol-1-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-pyrazol-1-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.6):

3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isooxazol-5-yl]-2-methyl-propionicacid

2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionicacid

2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionicacid

2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-isoxazol-5-yl}-propionicacid

2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid

2-Allyloxycarbonylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazol-5-yl}-propionicacid

2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-isoxazol-5-yl)-propionicacid

2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid

2-Acetylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-isothiazol-5-yl}-propionicacid

2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionicacid

2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionicacid

2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid

2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid

2-Formylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-isoxazol-5-yl}-propionicacid

2-Acetylamino-3-3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isothiazol-5-yl}-propionicacid

3-Acetylamino-3-(5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-2H-pyrazol-3-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazol-5-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.7):

3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-yl]-2-methyl-propionicacid

2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-yl]-propionicacid

2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino3-methyl-butyl)-pyrazol-1-yl]-propionic acid

2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-pyrazol-1-yl}-propionicacid

2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionicacid

2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-pyrazol-1-yl)-propionicacid

2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionicacid

2-Formylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-pyrazol-1-yl}-propionicacid

2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrazol-1-yl)-propionicacid

2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrazol-1-yl)-propionicacid

2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionicacid

2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionicacid

2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-pyrazol-1-yl}-propionicacid

2-Acetylamino-3-{3-[([3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrazol-1-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrazol-1-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.8):

3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-2-methyl-propionicacid

2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-propionicacid

2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-propionicacid

2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-oxazol-2-yl}-propionicacid

2,2-Dimethyl-3-[4-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionicacid

2-Allyloxycarbonylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionicacid

2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-2-yl)-propionicacid

2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionicacid

2-Formylamino-3-{4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiazol-2-yl}-propionicacid

2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-2-yl)-propionicacid

2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-2-yl)-propionicacid

2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionicacid

2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionicacid

2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-oxazol-2-yl}-propionicacid

2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-thiazol-2-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionicacid

2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-1H-imidazol-2-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.9):

3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-imidazol-1-yl]-2-methyl-propionicacid

2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-imidazol-1-yl]-propionicacid

2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-imidazol-1-yl]-propionicacid

2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-imidazol-1-yl}-propionicacid

2,2-Dimethyl-3-[4-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-imidazol-1-yl]-propionicacid

2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-imidazol-1-yl)-propionicacid

2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-imidazol-1-yl]-propionicacid

2-Formylamino-3-{4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-imidazol-1-yl}-propionicacid

2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-imidazol-1-yl)-propionic acid

2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-imidazol-1-yl)-propionicacid

2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-imidazol-1-yl]-propionicacid

2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-imidazol-1-yl]-propionicacid

2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-imidazol-1-yl}-propionicacid

2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-imidazol-1-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-imidazol-1-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.10):

3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-[1,2,4]oxadiazol-5-yl]-2-methyl-propionicacid

2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-[1,2,4]oxadiazol-5-yl]-propionicacid

2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-[1,2,4]oxadiazol-5-yl]-propionicacid

2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-[1,2,4]oxadiazol-5-yl}-propionicacid

2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]oxadiazol-5-yl]-propionicacid

2-Allyloxycarbonylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]oxadiazol-5-yl}-propionicacid

2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-[1,2,4]oxadiazol-5-yl)-propionicacid

2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]oxadiazol-5-yl]-propionicacid

2-Formylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-[1,2,4]thiadiazol-5-yl}-propionicacid

2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-[1,2,4]oxadiazol-5-yl)-propionicacid

2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-[1,2,4]oxadiazol-5-yl)-propionicacid

2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]oxadiazol-5-yl]-propionicacid

2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]oxadiazol-5-yl]-propionicacid

2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]oxadiazol-5-yl}-propionicacid

2-Formylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]thiadiazol-5-yl}-propionicacid

3-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-2H-[1,2,4]triazol-3-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]oxadiazol-5-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.11):3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino)-3-methyl-butyl)-[1,2,4]triazol-1-yl]-2-methyl-propionicacid

2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-[1,2,4]triazol-1-yl]-propionicacid

2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-[1,2,4]triazol-1-yl]-propionicacid

2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-[1,2,4]triazol-1-yl}-propionicacid

2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]triazol-1-yl]-propionicacid

2-Allyloxycarbonylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]triazol-1-yl}-propionicacid

2-(Butane-1-sulfonylamino)-3-(3-{[methyl-(4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-[1,2,4]triazol-1-yl)-propionicacid

2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]triazol-1-yl]-propionicacid

2-Acetylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-[1,2,4]triazol-1-yl}-propionicacid

2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-[1,2,4]triazol-1-yl)-propionicacid

2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-[1,2,4]triazol-1-yl)-propionicacid

2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]triazol-1-yl]-propionicacid

2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]triazol-1-yl]-propionicacid

2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-[1,2,4]triazol-1-yl}-propionicacid

2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]triazol-1-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]triazol-1-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.12):3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-2-yl]-2-methyl-propionicacid

2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-furan-2-yl]-propionicacid

2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-2-yl]-propionicacid

2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-1H-pyrrol-2-yl}-propionicacid

2,2-Dimethyl-3-[4-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl-pyrrolidin-2-yl)-thiophen-2-yl]-propionicacid

2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-furan-2-yl)-propionicacid

2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-2-yl]-propionicacid

2-Formylamino-3-{4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiophen-2-yl}-propionicacid

2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-1H-pyrrol-2-yl)propionicacid

2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-furan-2-yl)-propionicacid

2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiophen-2-yl]-propionicacid

2-Methanesulfonylamino-3-[4-(3-methyl-1-{([5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-2-yl]-propionicacid

2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-1H-pyrrol-2-yl}-propionicacid

2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-thiophen-2-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-furan-2-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.13):

3-[5-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-3-yl]-2-methyl-propionicacid

2-Acetylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-furan-3-yl]-propionicacid

2-Methanesulfonylamino-3-[5-({2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-3-yl]-propionicacid

2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-1H-pyrrol-3-yl}-propionicacid

2,2-Dimethyl-3-[5-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-thiophen-3-yl]-propionicacid

2-(Butane-1-sulfonylamino)-3-(5-{[methyl-(4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl-furan-3-yl)-propionicacid

2-Methyl-3-[5-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-3-yl]-propionicacid

2-Formylamino-3-{5-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiophen-3-yl}-propionicacid

2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-1H-pyrrol-3-yl)-propionicacid

2-Benzenesulfonylamino-3-(5-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-furan-3-yl)-propionicacid

2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiophen-3-yl]-propionicacid

2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-3-yl]-propionicacid

2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-2-methyl-1H-pyrrol-3-yl}-propionicacid

2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-thiophen-3-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-furan-3-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.14):

3-[5-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-2-yl]-2-methyl-propionicacid

2-Acetylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-furan-2-yl]-propionicacid

2-Methanesulfonylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-2-yl]-propionicacid

2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-1H-pyrrol-2-yl}-propionicacid

2,2-Dimethyl-3-[5-(1-[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-thiophen-2-yl]-propionicacid

2-(Butane-1-sulfonylamino)-3-(5-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-furan-2-yl)-propionicacid

2-Methyl-3-[5-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-2yl]-propionicacid

2-Formylamino-3-{5-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiophen-2-yl}-propionicacid

2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-1H-pyrrol-2-yl)-propionicacid

2-Benzenesulfonylamino-3-(5-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-furan-2-yl)-propionicacid

2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiophen-2-yl]-propionicacid

2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-2-yl]-propionicacid

2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-2-methyl-1H-pyrrol-2-yl}-propionicacid

2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-thiophen-2-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-furan-2-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.15):

3-[5-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isooxazol-3-yl]-2-methyl-propionicacid

2-Acetylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-3-yl]-propionicacid

2-Methanesulfonylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-3-yl]-propionicacid

2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-isoxazol-3-yl}-propionicacid

2,2-Dimethyl-3-[5-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-isoxazol-3-yl]-propionicacid

2-Allyloxycarbonylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazol-3-yl}-propionicacid

2-(Butane-1-sulfonylamino)-3-(5-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-isoxazol-3-yl)-propionicacid

2-Methyl-3-[5-(1-{([4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-3-yl]-propionicacid

2-Acetylamino-3-{5-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-isothiazol-3-yl}-propionicacid

2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-3-yl)-propionicacid

2-Benzenesulfonylamino-3-(5-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-3-yl)-propionicacid

2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-3-yl]-propionicacid

2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-isoxazol-3-yl]-propionicacid

2-Formylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-isoxazol-3-yl}-propionicacid

2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isothiazol-3-yl}-propionicacid

3-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-2H-pyrazol-5-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazol-3-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.16):

3-[5-(-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-2-methyl-propionicacid

2-Acetylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-propionicacid

2-Methanesulfonylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-propionicacid

2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-oxazol-2-yl}-propionicacid

2,2-Dimethyl-3-[5-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-2yl]-propionicacid

2-Allyloxycarbonylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionicacid

2-(Butane-1-sulfonylamino)-3-(5-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-2-yl)-propionicacid

2-Methyl-3-[5-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionicacid

2-Formylamino-3-{5-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiazol-2-yl}-propionicacid

2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-2-yl)-propionicacid

2-Benzenesulfonylamino-3-(5-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-2-yl)-propionicacid

2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionicacid

2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionicacid

2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-oxazol-2-yl}-propionicacid

2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-thiazol-2-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionicacid

2-Acetylamino3-[5-({2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-methyl)-1H-imidazol-2-yl]-propionicacid

Compounds which include the moiety of partial Formulas (1.1.17),(1.1.18) and (1.1.19):

2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-phenyl}-propionicacid

2-Formylamino-3-{6-[1-({3-methoxy-4-[3-(3-methyl-pyridin-2-yl)-ureido]-phenyl}-acetyl)-pyrrolidin-2-yl]-pyridin-2-yl}-propionicacid

3-{4-[1-({3-Ethyl-4-[3-(3-methyl-pyridin-2-yl)-ureido]-phenyl}-acetyl)-pyrrolidin-2-yl]-pyrimidin-2-yl}-propionicacid

2-Acetylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-phenyl]-propionicacid

2-Acetylamino-3-[3-({2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-methyl)-phenyl]-propionicacid

2-{2-[({[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyridin-4-ylmethyl}-4-methyl-pentanoicacid

3-{2-[(Methyl-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-methyl]-pyridin-4-yl}-propionicacid

2-Methanesulfonylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,3,5]triazin-2-yl}-propionicacid

1-[4-(1-{[6-(3-Pyridin-2-yl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-pyridin-2-ylmethyl]-cyclopropanecarboxylicacid

3-[3-(1-{[6-(3-Pyridin-2-yl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-phenyl]-butyricacid

2-(Butane-1-sulfonylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-phenyl}-propionicacid

2-Benzenesulfonylamino-3-[3-({[(2-methoxy-2′-methyl-biphenyl-4-yl)-acetyl]-methyl-amino}-methyl)-phenyl]-propionicacid

Compounds which include the moiety of partial Formula (1.1.20):

3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrrol-1-yl]-2-methyl-propionicacid

2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrrol-1-yl]-propionicacid

2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrrol-1-yl]-propionicacid

2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-pyrrol-1-yl}-propionicacid

2,2-Dimethyl-3-[4-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-pyrrol-1yl]-propionicacid

2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-pyrrol-1-yl)-propionicacid

2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-pyrrol-1-yl]-propionicacid

2-Formylamino-3-{4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-pyrrol-1-yl}-propionicacid

2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrrol-1-yl)-propionicacid

2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrrol-1-yl)-propionicacid

2-Benzenesulfonylamino-3-[4-(1-{[³-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-pyrrol-1-yl]-propionicacid

2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-pyrrol-1-yl]-propionicacid

2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-pyrrol-1-yl}-propionicacid

2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrrol-1-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrrol-1-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.21):

3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-yl]-2-methyl-propionicacid

2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-yl]-propionicacid

2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-yl]-propionicacid

2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-pyrazol-1-yl}-propionicacid

2,2-Dimethyl-3-[4-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl-pyrrolidin-2-yl)-pyrazol-1-yl]-propionicacid

2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-pyrazol-1-yl)-propionicacid

2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionicacid

2-Formylamino-3-{4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-pyrazol-1-yl}-propionicacid

2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrazol-1-yl)-propionicacid

2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrazol-1-yl)-propionicacid

2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionicacid

2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionicacid

2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-pyrazol-1-yl}-propionicacid

2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrazol-1-yl}-propionicacid

2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrazol-1-yl}-propionicacid

Compounds which include the moiety of partial Formula (1.1.22):

2-[({[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-benzooxazole-6-carboxylicacid

2-[1-(2-3-Methoxy-4-[3-(3-methyl-pyridin-2-yl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-3H-benzoimidazole-5-carboxylicacid

2-(1-{[4-(3-Pyridin-2-yl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxylicacid

2-(1-{[3-Ethoxy-4-(3-pyridin-2-yl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-benzothiazole-6-carboxylicacid

2-[({[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-benzothiazole-6-carboxylicacid

2-({[(4-Benzyloxy-phenyl)-acetyl]-methyl-amino}-methyl)-oxazolo[5,4]pyridine-5-carboxylicacid

3-Methyl-2-{1-[(4-phenoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-benzoimidazole-5-carboxylicacid

The above-described compounds of the present invention may be utilizedin the form of acids, esters, or other chemical classes of compounds towhich the compounds described belong. It is also within the scope of thepresent invention to utilize those compounds in the form ofpharmaceutically acceptable salts derived from various organic andinorganic acids and bases in accordance with procedures well known inthe art. Such well-known pharmaceutically acceptable salts include, butare not limited to acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, besylate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecysulfate,ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate,hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate,hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,isethionate, lactate, lactobionate, maleate, mandelate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,oleate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate,picrate, pivalate, propionate, salicylate, sodium phosphate, stearate,succinate, sulfate, sulfosalicylate, tartrate, thiocyanate, thiomalate,tosylate, and undecanoate.

Base salts of the compounds of the present invention include, but arenot limited to ammonium salts; alkali metal salts such as sodium andpotassium; alkaline earth metal salts such as calcium and magnesium;salts with organic bases such as dicyclohexylamine, meglumine,N-methyl-D-glucamine, tris-(hydroxymethyl)-methylamine (tromethamine),and salts with amino acids such as arginine, lysine, etc. Compounds ofthe present invention which comprise basic nitrogen-containing groupsmay be quaternized with such agents as (C₁-C₄) alkyl halides, e.g.,methyl, ethyl, iso-propyl and tert-butyl chlorides, bromides andiodides; di(C₁-C₄) alkyl sulfate, e.g., dimethyl, diethyl and diamylsulfates; (C₁₀-C₁₈) alkyl halides, e.g., decyl, dodecyl, lauryl,myristyl and and stearyl chlorides, bromides and iodides; andaryl-(C₁-C₄) alkyl halides, e.g., benzyl chloride and phenethyl bromide.Such salts permit the preparation of both water-soluble and oil-solublecompounds of the present invention.

Among the above-recited pharmaceutical salts those which are preferredinclude, but are not limited to acetate, mesylate, citrate, fumarate,gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide,isothionate, mandelate, meglumine, nitrate, oleate, phosphonate,pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate,tartrate, thiomalate, tosylate, and trimethylamine.

Multiple salts forms are included within the scope of the presentinvention where a compound of the present invention contains more thanone group capable of forming such pharmaceutically acceptable salts.Examples of typical multiple salt forms include, but are not limited tobitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium,and trihydrochloride.

The pharmaceutical compositions of the present invention comprise anyone or more of the above-described inhibitory compounds of the presentinvention, or a pharmaceutically acceptable salt thereof as alsoabove-described, together with a pharmaceutically acceptable carrier inaccordance with the properties and expected performance of such carrierswhich are well-known in the pertinent art.

The term “carrier” as used herein includes acceptable diluents,excipient, adjuvants and vehicles. Pharmaceutically acceptable carriersthat may be used in the pharmaceutical compositions of this inventioninclude but are not limited to, ion exchange compositions; alumina;aluminum stearate; lecithin; serum proteins, e.g., human serum albumin;phosphates; glycine; sorbic acid; potassium sorbate; partial glyceridemixtures of saturated vegetable fatty acids; water; salts orelectrolytes, e.g., prolamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidalsilica; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-basedsubstances; e.g., sodium carboxymethylcellulose; polyethylene glycol;polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; andwool fat.

More particularly, the diluents, excipient, adjuvants and vehicles usedin the pharmaceutical compositions of the present invention comprisemembers selected from the groups consisting essentially of thefollowing: acidifying and alkalizing agents added to obtain a desired orpredetermined pH comprise acidifying agents, e.g., acetic acid, glacialacetic acid, malic acid, and propionic acid, and alkalizing agents,e.g., edetol, potassium carbonate, potassium hydroxide, sodium borate,sodium carbonate, and sodium hydroxide; aerosol propellants requiredwhere the pharmaceutical composition is to be delivered as an aerosolunder significant pressure, e.g., acceptable halogenated hydrocarbons;nitrogen; or a volatile hydrocarbon such as butane, propane, isobutaneor mixtures thereof; antimicrobial agents including antibacterial,antifungal and antiprotozoal agents added where the pharmaceuticalcomposition is topically applied, e.g., antimicrobial agents such asbenzyl alcohol, chlorobutanol, phenylethyl alcohol, phenylmercuricacetate, potassium sorbate, and sorbic acid, and antifungal agents suchas benzoic acid, butylparaben, ethylparaben, methylparaben,propylparaben, and sodium benzoate; antimicrobial preservatives added tothe pharmaceutical compositions in order to protect them against thegrowth of potentially harmful microorganisms, e.g., alkyl esters ofp-hydroxybenzoic acid, propionate salts, phenoxyethanol, methylparabensodium, propylparaben sodium, sodium dehydroacetate, benzalkoniumchloride, benzethonium chloride, and benzyl alcohol; antioxidants addedto protect all of the ingredients of the pharmaceutical composition fromdamage or degradation by oxidizing agents present in the compositionitself or the use environment, e.g., anoxomer, ascorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorousacid, potassium metabisulfite, propyl octyl and dodecyl gallate, sodiummetabisulfite, sulfur dioxide, and tocopherols; buffering agents used tomaintain a desired pH of a composition once established, e.g., calciumacetate, potassium metaphosphate, potassium phosphate monobasic, andtartaric acid; and chelating agents used to help maintain the ionicstrength of the pharmaceutical composition and bind to and effectivelyremove destructive compounds and metals, e.g., edetate dipotassium,edetate disodium, and edetic acid.

Dermatologically active agents are added to the pharmaceuticalcompositions of the present invention to be applied topically, e.g.,wound healing agents such as peptide derivatives, yeast, panthenol,hexylresorcinol, phenol, tetracycline hydrochloride, lamin and kinetin,glucocorticosteroids for treating inflammation, e.g., hydrocortisone,dexamethasone, betamethasone, triamcinolone, fluocinolone andmethylprednisolone, retinoids for treating acne, psoriasis, cutaneousaging, and skin cancer, e.g., retinol, tretinoin, isotretinoin,etretinate, acitretin, and arotinoid, immunosuppressive agents fortreating inflammation, e.g., dapsone and sulfasalazine; mildantibacterial agents, e.g., resorcinol, salicylic acid, benzoylperoxide, erythromycin-benzoyl peroxide, erythromycin, clindamycin, andmupirocin, antifungal agents, e.g., griseofulvin, azoles such asmiconazole, econazole, itraconazole, fluconazole, and ketoconazole, andallylamines such as naftifine and terfinafine, antiviral agents, e.g.,acyclovir, famciclovir, and valacyclovir, antihistamines, e.g.,diphenhydramine, terfenadine, astemizole, loratadine, cetirizine,acrivastine, and temelastine, topical anesthetics, e.g., benzocaine,lidocaine, dibucaine, and pramoxine hydrochloride, topical analgesics,e.g., methyl salicylate, camphor, menthol, and resorcinol; topicalantiseptics for preventing infection, e.g., benzalkonium chloride andpovidone-iodine; vitamins and derivatives thereof such as tocopherol,tocopherol acetate, retinoic acid and retinol.

Further examples of diluents, excipient, adjuvants and vehicles used inthe pharmaceutical compositions of the present invention comprisemembers selected from the groups consisting essentially of thefollowing: dispersing and suspending agents, e.g., poligeenan, povidone,and silicon dioxide; emollients, e.g., hydrocarbon oils and waxes,triglyceride esters, acetylated monoglycerides, methyl and other alkylesters of C₁₀-C₂₀ fatty acids, C₁₀-C₂₀ fatty acids, C₁₀-C₂₀ fattyalcohols, lanolin and derivatives, polyhydric alcohol esters such aspolyethylene glycol (200-600), polyoxyethylene sorbitan fatty acidesters, wax esters, phospholipids, and sterols; emulsifying agents usedfor preparing oil-in-water emulsions; excipients, e.g., laurocapram andpolyethylene glycol monomethyl ether; humectants, e.g., sorbitol,glycerin and hyaluronic acid; ointment bases, e.g., petrolatum,polyethylene glycol, lanolin, and poloxamer; penetration enhancers,e.g., dimethyl isosorbide, diethyl-glycol-monoethylether,1-dodecylazacycloheptan-2-one, and dimethylsulfoxide (DMSO);preservatives, e.g., benzalkonium chloride, benzethonium chloride, alkylesters of p-hydroxybenzoic acid, hydantoin derivatives, cetylpyridiniumchloride, propylparaben, quaternary ammonium compounds such as potassiumbenzoate, and thimerosal; sequestering agents comprising cyclodextrins;solvents, e.g., acetone, alcohol, amylene hydrate, butyl alcohol, cornoil, cottonseed oil, ethyl acetate, glycerin, hexylene glycol, isopropylalcohol, isostearyl alcohol, methyl alcohol, methylene chloride, mineraloil, peanut oil, phosphoric acid, polyethylene glycol, polyoxypropylene15 stearyl ether, propylene glycol, propylene glycol diacetate, sesameoil, and purified water; stabilizers, e.g., calcium saccharate andthymol; surfactants, e.g., lapyrium chloride; laureth 4, i.e.,α-dodecyl-ω-hydroxy-poly(oxy-1,2-ethanediyl) or polyethylene glycolmonododecyl ether.

According to this invention, the pharmaceutical compositions may be inthe form of a sterile injectable preparation, for example a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as do naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant,such as Rh, HClX or similar alcohol.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added. Alternatively, thepharmaceutical compositions of this invention may be administered in theform of suppositories for rectal administration. These can be preparedby mixing the agent with a suitable non-irritating excipient which issolid at room temperature but liquid at the rectal temperature andtherefore will melt in the rectum to release the drug. Such materialsinclude cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation, as described above, or in a suitableenema formulation. Topically active transdermal patches may also beused.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspension in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation through the use of anebulizer, a dry powder inhaler or a metered dose inhaler. Suchcompositions are prepared according to techniques well-known in the artof pharmaceutical formulation and may be prepared as solutions insaline, employing benzyl alcohol or other suitable preservatives,absorption promoters to enhance bioavailability, hydrofluorocarbons,and/or other conventional solubilizing or dispersing agents.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated, and the particular mode of administration. It should beunderstood, however, that a specific dosage and treatment regimen forany particular patient will depend upon a variety of factors, includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, rate of excretion,drug combination, and the judgment of the treating physician and theseverity of the particular disease being treated. The amount of activeingredient may also depend upon the therapeutic or prophylactic-agent,if any, with which the ingredient is co-administered.

The dosage and dose rate of the compounds of this invention effectivefor preventing, inhibiting, suppressing or reducing cell adhesion andconsequent or associated pathogenic processes subsequently mediated byVLA-4 will depend on a variety of factors, such as the nature of theinhibitor, the size of the patient, the goal of the treatment, thenature of the pathology to be treated, the specific pharmaceuticalcomposition used, and the observations and conclusions of the treatingphysician.

For example, where the dosage form is oral, e.g., a tablet or capsule,suitable dosage levels of the compounds of Formula (1.0.0) will bebetween about 1.0 μg and about 10.0 mg/kg body weight per day,preferably between about 5.0 μg and about 5.0 mg/kg body weight per day,more preferably between about 10.0 μg and about 1.0 mg/kg of body weightper day, and most preferably between about 20.0 μg and about 0.5 mg/kgof body weight per day of the active ingredient.

Where the dosage form is topically administered to the bronchia andlungs, e.g., by means of a powder inhaler or nebulizer, suitable dosagelevels of the compounds of Formula (1.0.0) will be between about 0.1 μgand about 1.0 mg/kg body weight per day, preferably between about 0.5 μgand about 0.5 mg/kg body weight per day, more preferably between about1.0 μg and about 0.1 mg/kg of body weight per day, and most preferablybetween about 2.0 μg and about 0.05 mg/kg of body weight per day of theactive ingredient.

Using representative body weights of 10 kg and 100 kg in order toillustrate the range of daily topical dosages which might be used asdescribed above, suitable dosage levels of the compounds of Formula(1.0.0) will be between about 1.0-10.0 μg and 10.0-100.0 mg per day,preferably between about 5.0-50.0 μg and 5.0-50.0 mg per day, morepreferably between about 10.0-100.0 μg and 1.0-10.0 mg per day, and mostperferably between about 20.0-200.0 μg and about 0.5-5.0 mg per day ofthe active ingredient comprising a compound of Formula (1.0.0). Theseranges of dosage amounts represent total dosage amounts of the activeingredient per day for a given patient. The number of times per day thata dose is administered will depend upon such pharmacological andpharmacokinetic factors as the half-life of the active ingredient, whichreflects its rate of catabolism and clearance, as well as the minimaland optimal blood plasma or other body fluid levels of said activeingredient attained in the patient which are required for therapeuticefficacy

Numerous other factors must also be considered in deciding upon thenumber of doses per day and the amount of active ingredient per dosewhich will be administered. Not the least important of such otherfactors is the individual respsonse of the patient being treated. Thus,for example, where the active ingredient is used to treat or preventasthma, and is administered topically via aerosol inhalation into thelungs, from one to four doses consisting of acuations of a dispensingdevice, i.e., “puffs” of an inhaler, will be administered each day, eachdose containing from about 50.0 μg to about 10.0 mg of activeingredient.

Included within the scope of the present invention are embodimentscomprising compositions which contain, in addition to a compound of thepresent invention as active ingredient, additional therapeutic agentactive ingredients selected from the group consisting essentially ofanti-inflammatory corticosteroids; bronchodilators; antiasthmatics;non-steroidal anti-inflammatories; immunosuppressants; immunostimulants;antimetabolites; antipsoriatics and antidiabetics. Specific compoundswithin each of these classes may be selected from those listed under theappropriate headings in Comprehensive Medicinal Chemistry, PergamonPress, Oxford, England, pp. 970-986 (1990); and Goodman and Gilman's ThePharmacological Basis of Therapeutics, 9th ed., Hardman, J. G. andLimbird, L. E., eds., McGraw-Hill, 1996, the disclosure of which areincorporated herein by reference in their entireties. Especiallypreferred active ingredients to be included for use in combination withthe compounds of Formula (1.0.0) are anti-inflammatory compounds such astheophylline, sulfasalazine and aminosalicylates; immunosuppressantssuch as cyclosporin, FK-506, and rapamycin; antimetabolites such ascyclophosphamide and methotrexate; and immunomodulators such as theinterferons.

Still further embodiments of the present invention relate to a method oftreating or preventing an inflammatory, autoimmune or respiratorydisease by inhibiting cell adhesion and consequent or associatedpathogenic processes subsequently mediated by VLA-4. As alreadymentioned, VLA-4-associated cell adhesion plays a central role in avariety of inflammatory, immune and autoimmune diseases. Thus,inhibition of cell adhesion by the compounds of this invention may beutilized in methods of treating or preventing inflammatory, immune andautoimmune diseases. Preferably the diseases to be treated with themethods of this invention are selected from asthma, arthritis,psoriasis, transplantation rejection, multiple sclerosis, diabetes andinflammatory bowel disease.

The above-described methods of treatment of the present invention mayemploy the compounds of Formula (1.0.0) in the form of monotherapy, butsaid methods may also be used in the form of multiple therapy in whichone or more compounds of Formula (1.0.0) are coadministered incombination with a known anti-inflammatory, immunomodulating,immunostimulating or immunosuppressive agent. The terms “coadministered”or “coadministration” as used herein are intended to mean therapeuticutilization of one or more compounds of Formula (1.0.0) in combinationwith one or more additional therapeutic agents, including but notlimited to, administration of the combination of therapeutic activeagents in a single dosage form or in multiple dosage forms representingthe same or different routes of administration, said multiple dosageforms being administered at substantially the same time or at differenttimes.

Subsequent to synthesis of any of the above-recited preferred species ofthe present invention or any other compounds falling within the scope ofthe present invention, the biological activities relating to the VLA-4specificities of said compounds may be determined using one or more ofthe numerous in vitro and in vivo assays which have been describedheretofore in the technical literature pertinent to the art. Forexample, some of the now very-well established assay methods and modelsconcern measurement of VLA-4 activity by determining the concentrationof a test candidate inhibitor required to block the binding ofVLA-4-expressing cells to fibronectin- or CS-1 coated plates. In thisassay microtiter wells are coated with either fibronectin (containingthe CS-1 sequence), CS-1 peptide or soluble VCAM-1. Once the wells arecoated, varying concentrations of the test compound are then addedtogether with appropriately labelled, VLA-4-expressing cells.Alternatively, the test compound may be added first and allowed toincubate with the coated wells prior to the addition of the cells. Thecells are allowed to incubate in the wells for at least 30 minutes.Following incubation, the wells are emptied and washed. Inhibition ofbinding is measured by quantitating the fluorescence or radioactivitybound to the plate for each of the various concentrations of testcompound, as well as for controls containing no test compound. However,the assay just described is less preferred than other assays mentionedfurther below in determining the VLA-4 activity of the compounds ofFormula (1.0.0).

VLA-4-expressing cells that may be utilized in this assay include Ramoscells, Jurkat cells, A375 melanoma cells, as well as human peripheralblood lymphocytes (PBL). The cells used in this assay may befluorescently or radioactively labelled.

In order to assess the VLA-4 inhibitory specificity of test compounds,assays for other major groups of integrins, i.e., β₂ and β₃, as well asother β₁ integrins, such as VLA-5, VLA-6 and α₄β₇ may be performed.These assays may be similar to the adhesion inhibition and directbinding assays described above, substituting the appropriateintegrin-expressing cell and corresponding ligand. For example,polymorphonuclear cells (PMNs) express β₂ integrins on their surface andbind to ICAM; while β₃ integrins are involved in platelet aggregationand inhibition may be measured in a standard platelet aggregation assay.VLA-5 binds specifically to Arg-Gly-Asp sequences, while VLA-6 binds tolaminin. Further, α₄β₇ is a recently discovered homologue of VLA-4,which also binds fibronectin and VCAM as well as MAdCAM-1. Specificitywith respect to α₄β₇ is determined in a binding assay that utilizesCS-1, VCAM or MAdCAM-1 and a cell line that expresses α₄β₇, but notVLA-4, such as RPMI-8866 cells.

Once VLA-4-specific inhibitors are identified, they may be furthercharacterized in in vivo assays. One such assay tests the inhibition ofallergen induced airway hyperresponsiveness and cell influx, such asdescribed by Henderson et al., “Blockade of CD49d (α₄ integrin) onintrapulmonary but not circulating leukocytes inhibits airwayinflammation and hyperresponsiveness in a mouse model of asthma”, J.Clin. Invest., 100(12), pp. 3083-92 (1997). In this assay, mice aresensitized by ip exposure to an irritant, such as ovalbumin. Following arecovery period, the mice are challenged by aerosol exposure to theallergen. Before aerosol exposure, the mice are given various doses ofthe VLA-4 inhibitor by intratracheal injection. In vivo inhibition ofcell adhesion associated inflammation is assessed by measuring thenumber of cells and cytokines in the bronchial alveolar lavage fluid. Inthis manner, one may identify those inhibitors of this invention whichare best suited for inhibiting inflammation.

Another in vivo assay that may be employed is the primate asthma assay.This assay is performed essentially as described in Turner, C. R., etal., “Characterization of a primate model of asthma usinganti-allergy/anti-asthma agents”, Inflammation Research, 45(5), pp.239-45 (1996), the disclosure of which is incorporated herein byreference in its entirety. This assay measures inhibition of Ascarisantigen-induced late phase airway responses and airwayhyperresponsiveness in allergic primates following administration ofanti-allergy/anti-asthma agents.

The compounds of the present invention may be formulated intopharmaceutical compositions that may be administered orally,parenterally, by inhalation (metered dose inhaler, dry powder inhaler ornebulizer), topically, rectally, nasally, intraocularly, buccally,vaginally or via an implanted reservoir. The term “parenteral” as usedherein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques.

The compounds of Formula (1.0.0) may be prepared in accordance withwell-known procedures for carrying out the synthesis of organiccompounds which are non-peptidyl or semi-peptidyl in nature. A number ofdifferent procedures are available which are fully disclosed in thetechnical literature and with which the skilled artisan will befamiliar. The description which follows of several such synthesisschemes is merely representative and not intended to be in any waylimiting. A number of abbreviations are used in said description inorder to conserve space. Although these abbreviations are also wellknown to the artisan, they are set out immediately below for clarity andconvenience:

BOP benzotriazol-1-yloxy-tris(dimethylamino) phosphoniumhexafluorophosphate DAST diethylaminosulfur trifluoride DIEAdiisopropylethyl amine DMF Dimethylformamide EDCI1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride HOBT1-hydroxybenzotriazole THF tetrahydrofuran

The synthesis of compounds of the Formula 1.0.0 in which the “B”component is an isoxazole ring and the “Y” component is —SO₂— isillustrated in Scheme 1, steps A through G. In Scheme 1, step A, thestarting material, diethyl amino malonate, is commercially available,e.g., from Aldrich Chemical Company, Milwaukee, Wis. 53233. The amideproduct (2.0.1), where R⁵ is hydrogen, methyl or phenyl, is alsocommercially available. Other amides, where R⁵ is alkyl, aryl,heterocyclyl or heteroaryl are made readily available by the reaction ofthe appropriate acid chloride with the amine (2.0.0) using theconditions that are well described in the literature (e.g. March, J.“Advanced Organic Chemistry”, 3^(rd) edition, 1985). Under similarconditions, the amine (2.0.0) may be converted to its correspondingsulfonamide by the reaction of 2.0.0 with an alkyl or aryl sulfonylchloride. The carbamate product (2.0.1), where R⁵ is alkoxy or aryloxyis prepared from amine 2.0.0 in accordance with procedures described byPaik, Yi Hyon; Dowd, Paul; J. Org. Chem. 1986, 51(15), 2910-2913; andKawai, Masao; Nyfeler, Rolf; Berman, Judd M.; Goodman, Murray; J. Med.Chem., 1982 25(4), 397-402.

In Scheme 1, Step B, the intermediate 2.0.3 is prepared from the oxime2.0.2. Oxime 2.0.2 is prepared from its corresponding aldehyde byprocedures well known to those skilled in the art (e.g. Chung, Yong Jun;Ryu, Eun Jung; Keum, Gyochang; Kim, Byeang Hyean; Bioorg.Med.Chem.;1996, 4(2) 209-226; and Kim, Byeang Hyean; Chung, Yong Jun; Keum,Gyochang; Kim, Jaheon; Kim, Kimoon; Tetrahedron Lett.; 1992, 33(45);6811-6814). Oxime 2.0.2 is converted to the isoxazole 2.0.3 by oxidationwith a suitable oxidant such as sodium hypochlorite, tert-butylhypochlorite, or N-chlorosuccinimide in a suitable solvent such as THF,chloroform or methylene chloride; and reacting the resulting nitrileN-oxide in situ with propargyl bromide. This [2+3] cycloadditionreaction is well known in the literature as a method for preparing theisoxazole ring structure. See, e.g., Synthesis, 508-9, 1982.

In Scheme 1, Step C, the bromide intermediate 2.0.3 is converted to theisoxazole containing component 2.0.4. The bromide 2.0.3 is reacted withan optionally substituted malonate (2.0.1) in a suitable solvent such asDMF, DMSO or methylene chloride, in the presence of a base such astriethlyamine or cesium carbonate. DMF is the preferred solvent andcesium carbonate is the preferred base. The reaction is performed at atemperature between 0 and 30° C. for a period of 1 to 16 hours. Thereaction of bromide 2.0.3 with malonate 2.0.1 in Scheme 1, step C, isnot limited to 2-amino malonates, but can be expanded to includemalonates of the formula [EtOC(═O)CHR⁷C(═O)OEt], where R⁷ is definedabove in the definition of Formula 1.0.0.

The synthesis of the mono ester intermediate 2.0.5 is illustrated inScheme 1, Step D. The diethyl malonate 2.0.4 is converted to itshalf-ester intermediate by reaction with one equivalent of a suitablebase such as aqueous sodium hydroxide or lithium hydroxide in a solventsuch as THF, methanol, tert-butanol or dioxane. The use of aqueoussodium hydroxide in dioxane is preferred. The reaction is conducted at atemperature between 0 and 50° C. for a time period of between 1 and 16hours. Three hours at ambient temperature is preferred. This half-esterintermediate is subsequently transformed to mono ester 2.0.5 in situ byheating it in a suitable solvent such as benzene, toluene or dioxane ata temperature between 0 and 200° C. for a time period of between 1 and16 hours. Heating at 125° C. for 3 hours in dioxane is preferred.

The synthesis of the amine intermediate 2.0.6 is illustrated in Scheme1, Step E. The tert-butyloxycarbamate intermediate 2.0.5 is reacted withan acid such as neat trifluoroacetic acid, or a solution hydrochloricacid in a suitable non-aqueous solvent such as dioxane. The reaction isconducted at a temperature between 0 and 50° C. for a time period ofbetween 1 and 16 hours. Hydrochloric acid in dioxane at ambienttemperature for 1 hour is the preferred conditions. It will berecognized by those skilled in the art that the tert-butyloxycarbonylgroup serves as a protecting group for the amine and that other suitableprotecting groups can be employed. It will be further recognized thatmethods for removal of these protecting groups must be compatible withall the functionality present in R⁵. These methods are well-known in thetechnical literature of the relevant art. For example, see Greene, T.W., Wuts, P. G. M. Protective Group in Organic Synthesis; John Wiley &Sons: New York, 1991.

The synthesis of the sulfonamide intermediate 2.0.7 is described inscheme 1 step F. The amine 2.0.6 is reacted with a sulfonyl chloride[A(CH₂)_(n)—SO₂Cl, where “A” and “n” are defined above in the definitionof formula 1.0.0] in a solvent such as dichloromethane, water, orpyridine with or without a base such as sodium carbonate ordiisopropylethylamine. The reaction is conducted at a temperaturebetween 0 and 50° C. for a period of between 1 and 16 hours. Thepreferred conditions are sodium carbonate in water at ambienttemperature for 16 hours.

The carboxylic acid product is prepared from ester intermediate 2.0.7 asillustrated in scheme 1, step G. The ester intermediate 2.0.7 is reactedwith a suitable aqueous base, such as lithium hydroxide, potassiumhydroxide or sodium hydroxide in a solvent such as tert-butanol,methanol, and/or THF. The reaction is conducted at a temperature between0 and 50° C. for a time period between 0.5 and 24 hours. Aqueous lithiumhydroxide in a mixture of THF and methanol at ambient temperature for 1hour are the preferred conditions.

The above-described synthesis is broadly applicable to the compounds ofFormula (1.0.0). In order to make said synthesis even more clear, thereis set out below Synthesis Scheme 1-α, Steps A through G with referenceto a particular compound of the present invention:

The following schematic synthesis diagram illustrates a generalizedpreparation process for the compounds of Formula 1.0.0 in which the “Y”component is C═O:

The starting material A¹—NCO is an isocyanate in which “A¹” has the samedefinition as the A component of Formula (1.0.0) regarding the aryl,heteroaryl and heterocyclyl moieties substituted with 0 to 3 R⁹.Isocyanate starting materials for making component A, such as phenylisocyanate, o-tolyl isocyanate, 2-fluorophenyl isocyanate and2-chlorophenyl isocyanate are commercially available, e.g., from AldrichChemical Company, Milwaukee, Wis. 53233. Alternatively, isocyanatestarting materials can be readily prepared from their correspondingamines using the methods described in the literature (e.g. March, J.“Advanced Organic Chemistry”, 3^(rd) edition, 1985). Pyridyl analoguesof the above phenyl isocyanates can be used to prepare the correspondingcompounds of Formula (1.0.0) where the A component contains a pyridylgroup.

One of the above-described isocyantes is reacted with an amine offormula 2.0.10. The addition of amines to isocyanates is a well-knownreaction which provides substituted ureas in a facile manner. Thereaction can be carried out in a solvent such as methylene chloride withtriethylamine at slightly elevated temperatures. The disubstituted urea(2.0.11) prepared as in the above-indicated reaction scheme, which formsthe reactant eventually resulting in component A of the compounds ofFormula (1.0.0), is next reacted with an amine of the formula“—NR⁴CR²R³—B”, in which “B” is defined as one of the partial Formulas(1.1.0)-(1.1.22).

The reaction between the component A forming reactant (2.0.11) and theamine 2.0.6 will be recognized by the artisan as one involving theacylation of an amine by a carboxylic acid which can be made to proceedin good yield at room temperature or slightly above by the use ofcoupling agents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCl) and 1-hydroxybenzotriazole (HOBT);dicyclohexylcarbodiimide (DCCl); N,N′-carbonyldiimidazole;N,N,N′,N′-tetramethyl(succinimido)uronium tetrafluoroborate; andbenzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate(BOP). The amine component (2.0.6) is available as described inScheme 1. This reaction may be illustrated in the above schematicsynthesis diagram which provides a generalized preparation process forthe compounds of Formulas (1.0.0).

To prepare the final product of Formula (1.0.0) in the form of the acid,an additional step is required, as is shown in the following reactionscheme:

The final acid product (2.0.13) is prepared from ester 2.0.12 asillustrated in the above scheme. The intermediate is reacted with asuitable aqueous hydroxide base, such as lithium hydroxide, potassiumhydroxide or sodium hydroxide in a solvent system comprised oftert-butanol, methanol or THF and methanol. The reaction is conducted ata temperature between 0 and 50° C. for 0.5 to 16 hours. Lithiumhydroxide in THF, methanol, and water at ambient temperature for 1 hourare the preferred conditions.

The above-described synthesis is broadly applicable to the compounds ofFormula (1.0.0). In order to make said synthesis even more clear, thereis set out below Synthesis Scheme 2-α, Steps A through C with referenceto a particular compound of the present invention:

An alternative synthesis of compounds of the Formula (1.0.0) isillustrated in Synthesis Scheme 3, steps A through C. The synthesis ofthe amine intermediate 2.0.14 is illustrated in scheme 3, step A.Tert-butyloxycarbamate intermediate 2.0.4 is reacted with an acid suchas neat trifluoroacetic acid, or a solution hydrochloric acid in asuitable non-aqueous solvent such as dioxane. The reaction is conductedat a temperature between 0 and 50° C. for a time period of between 1 and16 hours. Hydrochloric acid in dioxane at ambient temperature for 1 hourare the preferred conditions. It will be recognized by those skilled inthe art that the tert-butyloxycarbonyl group serves as a protectinggroup for the amine and that other suitable protecting groups can beemployed. It will be further recognized that methods for removal ofthese protecting groups must be compatible with all of the functionalitypresent in R⁵. These methods are well-known in the technical literatureof the relevant art. For example, see Greene, T. W., Wuts, P. G. M.Protective Group in Organic Synthesis; John Wiley & Sons: New York,1991.

In scheme 3, step B, the amine 2.0.14 is reacted with acid 2.0.15 underthe same 15 conditions as synthesis Scheme 2, step B.

To prepare the final product of Formula (1.0.0) in the form of the acid,an additional step is required, as is shown in the following reactionscheme:

The final acid product (2.0.17) is prepared from ester 2.0.16 asillustrated in the above scheme. The intermediate is reacted with asuitable aqueous hydroxide base, such as lithium hydroxide, potassiumhydroxide or sodium hydroxide in a solvent system comprised oftert-butanol, methanol or THF and methanol. The reaction is conducted ata temperature between 0 and 50° C. for 0.5 to 16 hours. Lithiumhydroxide in THF, methanol, and water at ambient temperature for 1 hourare the preferred conditions.

The above-described synthesis is broadly applicable to the compounds ofFormula (1.0.0). In order to make said synthesis even more clear, thereis set out below Synthesis Scheme 3-α, Steps A through C with referenceto a particular compound of the present invention:

An alternative mode for the synthesis of compounds of the Formula(1.0.0) is illustrated in Synthesis Scheme 4, Steps A through D.

In Scheme 4, Step A, the oxime 2.0.2 is converted to the isoxazole2.0.18 by oxidation with a suitable oxidant such as sodium hypochlorite,tert-butyl hypochlorite, or N-chlorosuccinimide in a suitable solventsuch as THF, chloroform or methylene chloride; and reacting theresulting nitrile N-oxide in situ with a 2,2-disubstituted methylpent-4-ynoate. This [2+3] cycloaddition reaction is well known in theliterature as a method for preparing the isoxazole ring structure. See,e.g., Synthesis, 508-9, 1982.

The synthesis of the amine intermediate 2.0.19 is illustrated in theabove reaction scheme using the same conditions as Scheme 3, step A. Thestarting material is the tert-5 butyloxycarbamate intermediate 2.0.18.

In scheme 4, step C, the amine 2.0.19 is reacted with acid 2.0.15 underthe same conditions as synthesis Scheme 2, step B. This reaction may beillustrated in the above schematic synthesis diagram which provides ageneralized preparation process for the compounds of Formulas (1.0.0).

To prepare the final product of Formula (1.0.0) in the form of the acid,an additional step is required, as is shown in the following reactionscheme:

The final acid product 2.0.21 was prepared from ester 2.0.20 asillustrated in the above scheme using the method of Scheme 3, step C.

The above-described synthesis is broadly applicable to the compounds ofFormula (1.0.0). In order to make said synthesis even more clear, thereis set out below Synthesis Scheme 4-α, Steps A through C with referenceto a particular compound of the present invention:

An alternative mode for the synthesis of compounds of the Formula(1.0.0) is 5 illustrated in Synthesis Scheme 5 Steps A through D.

The bromide 2.0.22 is available commercially from, for example, fromAldrich Chemical Company, Milwaukee, Wis. 53233. Bromide 2.0.22 isconverted into the desired diester containing component 2.0.23, as shownin the above scheme. The bromide is reacted with an amino malonate underthe conditions described in scheme 1, step C.

The nitrile 2.0.23 is converted to the desired amine 2.0.24 asillustrated in the above reaction scheme. The nitrile 2.0.23 is reducedto the corresponding amine 2.0.24 by hydrogenation as described in theliterature (e.g. March, J. “Advanced Organic Chemistry”, 3^(rd) edition,1985).

The above-described synthesis is broadly applicable to the compounds ofFormula (1.0.0). In order to make said synthesis even more clear, thereis set out below Synthesis Scheme 5-α:

The synthesis of bicyclic compounds of the Formula (1.0.0) isillustrated in Synthesis Scheme 6 Steps A through D. Starting materialsare acids and amines available from commercial sources, eg., AldrichChemical Company, Milwaukee, Wis. 53233.

The reaction illustrated in the above scheme will be recognized by theartisan as one involving the acylation of an amine 2.0.22 by acarboxylic acid 2.0.23 which can be made to proceed in good yield atroom temperature or slightly above by the use of coupling agents such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) and1-hydroxybenzotriazole (HOBT); dicyclohexylcarbodiimide (DCCl);N,N′-carbonyldiimidazole; POCl₃; TiCl₄; SO₂ClF; Ti(OBu)₄; P₂I₄; Bu₃N;benzotriazol-1-yl diethyl phosphate;N,N,N′,N′-tetramethyl(succinimido)uronium tetrafluoroborate; andpreferably di-iso-propylethyl amine (DIEA) andbenzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate(BOP).

The synthesis of the amine intermediate 2.0.26 is illustrated in theabove reaction scheme. The starting material is a mixture of thetert-butyloxycarbamate intermediates 2.0.24 and 2.0.25. Intermediates2.0.24 and 2.0.25 are reacted with an acid such as hydrochloric acid oracetic acid with or without a suitable solvent such as dioxane. Thereaction is conducted at a temperature between 0 and 100° C. for 1 to 16hours. Acetic acid in the absence of additional solvent at 80° for 1.5hours is preferred. It will be recognized by those skilled in the artthat these conditions accomplish both the cyclization to form thedesired bicyclic ring system and removal of the tert-butyloxycarbonylgroup. It will also be recognized by those skilled in the art that thetert-butyloxycarbonyl group serves as a protecting group for the amineand that other suitable protecting groups can be employed. It will befurther recognized that methods for removal of these protecting groupsmust be compatible with all the functionality present in intermediate2.0.26. These methods are well-known in the technical literature of therelevant art. For example, see Greene, T. W., Wuts, P. G. M. ProtectiveGroup in Organic Synthesis; John Wiley & Sons: New York, 1991.

The above-described synthesis is broadly applicable to the compounds ofFormula (1.0.0). In order to make said synthesis even more clear, thereis set out below Synthesis Scheme 6-α, with reference to a particularcompound of the present invention:

An alternative mode for the synthesis of compounds of the Formula(1.0.0) is illustrated in Synthesis Scheme 7 Steps A through C. Thesesteps describe an alternative route to the B component used in thecoupling reaction as decribes in Synthesis Scheme 2 Step B.

The preparation of bromide intermediate 2.0.29 was described inSynthesis Scheme 1 Step A. The intermediate bromide 2.0.29 was reactedwith the commercially available imine 2.0.30 in a suitable solvent suchas toluene, methylene chloride or DMF with a base such as cesiumcarbonate, cesium hydroxide or potassium hydroxide in the presence of anadditive such as tertabutyl ammonium bromide, tetrabutyl ammoniumchloride, or tetraphenylammonium bromide. The reaction was performed ata temperature between −78 and 50° C. for a period of 1 to 16 hours. Thereaction of the bromide intermediate 2.0.29 with the imine 2.0.30 intoluene at ambient temperature in the presence of tetrabutylammoniumbromide for 1 hour was preferred.

The synthesis of the amine intermediate 2.0.32 is illustrated in theabove reaction scheme. The imine intermediate 2.0.31 can be transformedto the amine 2.0.32 by a variety of methods well known to those skilledin the art and described in the literature. For examples, Wolfe, JohnP.; Ahman, Jens; Sadighi, Joseph P.; Singer, Robert A.; Buchwald,Stephen L.; Tetrahedron Lett.; 1997, 38(36); 6367-6370; and Corey, E.J.; Xu, Feng,; Noe, Mark C.; J. Am. Chem, Soc., 1997, 119, 12414-12415.In the preferred method, intermediate imine 2.0.31 is treated with amixture of ethyl acetate and hydrochloric acid for three hours atambient temperature.

The synthesis of the amide intermediate 2.0.33 is illustrated in theabove reaction scheme. The amine with or without a solvent, such asdicloromethane, chloroform, benzene, water or pyridine is reacted withan acid anhydride or acid chloride with or without the addition of abase such as sodium carbonate, pyridine or diisopropyl ethyl amine. Thereaction is performed between 0 and 50° C. for a period of 1 to 16hours. The preferred conditions employ dichloromethane and pyridine atambient temperature for 16 hours.

The above-described synthesis is broadly applicable to the compounds ofFormula (1.0.0). In order to make said synthesis even more clear, thereis set out below Synthesis Scheme 7-α,:

EXEMPLIFICATION OF PREFERRED EMBODIMENTS

The examples which follow further illustrate the compounds, compositionsand methods of treatment of the present invention, but are not intendedto thereby limit the scope of the present invention. A numberabbreviations are used in the following examples in order to conservespace. Although these abbreviations are well known to the artisan, theyare set out immediately below for clarity and convenience of the reader:

BOP benzotriazol-1-yloxy-tris(dimethylamino) phosphoniumhexafluorophosphate DAST diethylaminosulfur trifluoride DIEAdiisopropylethyl amine DMF dimethylformamide EDCI1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride HOBT1-hydroxybenzotriazole THF tetrahydrofuran

EXAMPLE 1 A.2-Allyloxycarbonylamino-3-{3-[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-isoxazol-5yl}-propionicacid

A tetrahydrofuran (1.0 mL) and methanol (0.5 mL) solution of2-allyloxycarbonylamino-3-{3-[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-isoxazol-5-yl}-propionicacid ethyl ester (59 mg, 0.108 mmol) was stirred with 2M aqueous lithiumhydroxide (0.5 mL) at room temperature for 40 minutes. The reaction wasacidified to pH 1 with 1 M hydrochloric acid and extracted twice withethyl acetate. The combined extracts were dried over magnesium sulfateand concentrated in vacuo to give the title compound as a white solid(51 mg, 91%). MS (CI) m/z 518 (M+1).

B.2-Allyloxycarbonylamino-3-{3-[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-isoxazol-5-yl}-propionicacid ethyl ester

2-Allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-prop ionicacid ethyl ester hydrochloride(110 mg, 0.294 mmol) and sodium carbonate(93.5 mg, 0.882 mmol) were dissolved in water (1.5 mL) and3,5-dichlorobenzenesulfonylchloride (86.7 mg, 0.353 mmol) was added.This mixture was stirred overnight. The reaction was extracted twicewith dichloromethane. The combined organic portion was washed withbrine, dried over magnesium sulfate and concentrated in vacuo to yieldthe title compound (59 mg, 37%). MS (CI) m/z 545.7 (M+1)

C. 2-Allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionicacid ethyl ester hydrochloride

2-[5-(2-Allyloxycarbonylamino-2-ethoxycarbonyl-ethyl)-isoxazol-3-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (3.44 g, 7.86 mmol) was dissolved in 4Mhydrochloric acid in dioxane (10 mL) and stirred at room temperature for2 hours. The reaction was then concentrated in vacuo and co-evaporatedwith dichloromethane to give the desired product as a brown waxy solid.MS (CI) m/z 509.9 (M+1)

D.2-[5-(2-Allyloxycarbonylamino-2-ethoxycarbonyl-ethyl)-isoxazol-3-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

A mixture of2-allyloxycarbonylamino-2-[3-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonicacid monoethyl ester and2-allyloxycarbonylamino-2-[3-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonicacid diethyl ester (10.4 g, 21.5 mmol) was dissolved in dioxane (130 mL)and heated in an oil bath to 125° C. for 3 hours. The dioxane was thenremoved in vacuo. The residue was dissolved in ethyl acetate, washedwith saturated sodium carbonate and brine, dried over magnesium sulfateand concentrated. The crude material was chromatographed on a BiotageFlash 40M column eluting with ethyl acetate/hexanes (1:4) to give thetitle compound as a clear oil (5.12 g, 56% 2 steps). MS (CI) m/z 338.0(M-99).2-Allyloxycarbonylamino-2-[3-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonicacid diethyl ester was recovered (2.96 g, 27%). MS (CI) m/z 509.9 (M+1),409.9 (M−99)

E.2-Allyloxycarbonylamino-2-[3-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonicacid monoethyl ester

Sodium hydroxide, 1M, (21.5 mL, 21.5 mmol) was added in portions over 30minutes to a dioxane (22 mL) solution of2-allyloxycarbonylamino-2-[3-(1-tert-butoxycarbonylpyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonicacid diethyl ester (10.95 g, 21.5 mmol). After stirring overnight, thereaction had not gone to completion. An additional 0.2 equivalents of 1Msodium hydroxide (4.2 mL, 4.2 mmol) was added and stirring continued for3 hours. The reaction was diluted with ethyl acetate (50 mL) and 1Msulfuric acid (23 mL) was added dropwise at 0° C. The aqueous portionwas extracted twice with ethyl acetate. The combined organic portionswere dried over magnesium sulfate and concentrated in vacuo to give athe title compound. The crude product was used directly in the next stepwithout separation of the unreacted diester. MS (CI) m/z 382.2 (M−99).

F.2-Allyloxycarbonylamino-2-[3-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonicacid diethyl ester

A dimethyl formamide (260 mL) solution of2-(5-Bromomethyl-isoxazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butylester (7.29 g, 56 mmol) and 2-allyloxycarbonylamino-malonic acid diethylester (8.25 g, 32 mmol) was cooled to 0° C. and cesium carbonate (25.41g, 78 mmol) was added. The reaction was allowed to warm to roomtemperature and stirred for 3 hours.

The reaction mixture was then poured into diethyl ether (2 L) and washedwith water (5×200 mL) and brine. The organic portion was dried overmagnesium sulfate and concentrated in vacuo. The crude residue waschromatographed on silica gel eluting with ethyl acetate:hexane (3:7) toafford the title compound as a clear colorless oil (10.95 g; 83%). MS(CI) m/z 260.1 (M−99).

G. 2-Allyloxycarbonylamino-malonic acid diethyl ester

A methylene chloride (1.0 L) solution of diethylamino malonatehydrochloride (47.0 g, 226 mmol) was cooled to 0° C. and pyridine (45mL, 564 mmol) was added. Previously insoluble solid dissolved uponaddition of the pyridine. Allyl chloroformate (20 mL, 188 mmol) wasslowly added dropwise to maintain the temperature of the reaction below5° C. After the addition was complete, the reaction was stirred at 0° C.for 15 minutes. The reaction was washed with 1M hydrochloric acid (6×100mL), dried over magnesium sulfate and concentrated in vacuo to give thetitle compound as a white solid (46.78 g, 80%). The crude product wasused without further purification. MS (CI) m/z 260.1 (M+1)

H. 2-(5-Bromomethyl-isoxazol-3-yl)-pyrrolidine-1-carboxylic acidtert-butyl ester

The title compound was prepared in the manner described for examples 7Hand 7I, utilizing 2-(hydroxyimino-methyl)-pyrrolidine-1-carbamic acidtert-butyl ester in step 7I.

EXAMPLE 2 A.2-Allyloxycarbonylamino-3-(3-{1-[(4-nitro-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5propionicacid

The hydrolysis of2-allyloxycarbonylamino-3-(3-{1-[(4-nitro-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionicacid ethyl ester was carried out according to the same protocol as inExample 1A to afford the title compound. MS (CI) m/z 472.6 (M+1), 471.7(M−1).

B.2-Allyloxycarbonylamino-3-(3-{1-[(4-nitro-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5yl)-propionicacid ethyl ester

A dimethyl formamide (82 mL) solution of 4-nitrophenylacetic acid (1.61g, 8.87 mmol) in dimethyl formamide (82 mL) was stirred with4-hydroxybenzotriazole monohydrate (1.40 g, 10.4 mmol) for 10 minutes.1-(3-Dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride (1.86 g, 9.72mmol) was added and the mixture was stirred until all1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride haddissolved. To this solution,2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionicacid ethyl ester hydrochloride from Example 1C (3.16 g, 8.25 mmol) wasadded and the mixture stirred 30 minutes followed by addition oftriethyl amine (1.26 mL, 9.04 mmol). After the reaction had stirred atroom temperature over night it was poured into water and extracted withethyl acetate three times. The combined extracts were washed with asaturated solution of sodium bicarbonate, water (2×) and brine. Theorganic portion was dried over magnesium sulfate and concentrated. Theresulting residue was chromatographed on a Biotage Flash 40S columneluting with ethyl acetate/hexanes (5:1) to yield the title compound asa yellow oil (674 mg, 15%). MS (CI) m/z 501.3 (M+1). Additionally,starting material2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionicacid ethyl ester was recovered (2.15 9, 75%). MS (CI) m/z338.1 (M+1)

EXAMPLE 3 A.2-Allyloxycarbonylamino-3-[3-(1-{[4-(2,6-dichloro-benzoylamino)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid

The hydrolysis of2-allyloxycarbonylamino-3-[3-(1-{[4-(2,6-dichloro-benzoylamino)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid ethyl ester was carried out according to the same protocol as inexample 1A to afford the title compound (77 mg, 75%). MS (CI) m/z 616.7(M+1), 612.5 (M−1).

B.2-Allyloxycarbonylamino-3-[3-(1-{[4-(2,6-dichloro-benzoylamino)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid ethyl ester

A dichloromethane (1 mL) solution2-allyloxycarbonylamino-3-(3-{1-[(4-amino-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionicacid ethyl ester (80 mg, 0.170 mmol) was cooled to 0° C. and2,6-dichlorobenzoylchloride (39 mg, 0.187 mmol) was added. The mixturewas stirred for 15 minutes then pyridine (28 μL, 0.34 mmol)was added.The reaction was slowly warmed to room temperature and stirredovernight. The reaction was diluted with ethyl acetate and washed withwater, 1 M sodium hydroxide and brine. The organic portion was driedover magnesium sulfate and concentrated to give the title compound (84mg, 78%). MS (CI) m/z 635.3 (M+1), 632.5 (M−1)

C.2-Allyloxycarbonylamino-3-(3-{1-[(4-amino-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionicacid ethyl ester

A solution of2-allyloxycarbonylamino-3-(3-{1-[(4-nitro-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionicacid ethyl ester (2B) (565 mg, 1.13 mmol) and iron(0) powder (384 mg,6.98 mmol) in ethanol/water (5 mL, 1:1) was heated to reflux.Hydrochloric acid, 1M, (0.29 mL, 0.29 mmol) was added drop wise and thereaction was heated at reflux for 45 minutes. It was then neutralizedwith 1M sodium hydroxide and filtered through celite. The filtrate wasdiluted with ethyl acetate and washed with water and brine. The organicportion was dried over magnesium sulfate and concentrated in vacuo. Thecrude residue was chromatographed on a Biotage Flash 40S column elutingwith ethyl acetate/hexanes (6:1) to provide the title compound as ayellow oil (240 mg, 51%). MS (CI) m/z 471.0 (M+1)

EXAMPLE 4 A.2-Allyloxycarbonylamino-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid

The hydrolysis of2-allyloxycarbonylamino-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid ethyl ester was carried out according to the same protocol as inexample 1A to afford the title compound. MS (CI) m/z 576.0 (M+1), 573.9(M−1)

B.2-Allyloxycarbonylamino-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid ethyl ester

The title compound was prepared in the manner described in example 2Busing [4-(3-o-tolyl-ureido)-phenyl]-acetic acid MS (CI) m/z 604.0 (M+1).

EXAMPLE 5 A.3-(3-{1-[(4-Acetylamino-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-2-allyloxycarbonylamino-propionicacid

The hydrolysis of3-(3-{1-[(4-acetylamino-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-2allyloxycarbonylamino-propionicacid ethyl ester was carried out according to the same protocol as inexample 1A to afford the title compound. MS (CI) m/z 485.3 (M+1), 483.0(M−1)

B.3-(3-{1-[(4-Acetylamino-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-2-allyloxycarbonylamino-propionicacid ethyl ester

The title compound was prepared in the manner described in Example 3Busing acetyl chloride in place of 2,6-dichlorobenzoylchloride. MS (CI)m/z 513.0 (M+1).

EXAMPLE 6 A.2-tert-Butoxycarbonylamino-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl-isoxazol-5-yl]-propionicacid

The hydrolysis of2-tert-butoxycarbonylamino-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid methyl ester was carried out according to the protocol in example1A to afford the title compound. MS (CI) m/z 590.2 (M−1), 492.2 (M−99)

B.2-tert-Butoxycarbonylamino-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl-isoxazol-5-yl]-propionicacid methyl ester

A solution of1-(4-{2-[2-(hydroxyimino-methyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-phenyl)-3-o-tolyl-urea(300 mg, 0.789 mmol), 2-tert-butoxycarbonylamino-pent-4-ynoic acidmethyl ester (359 mg, 1.182 mmol, crude mixture) and triethyl amine(12.9 μL) in dichloromethane (2 mL) was stirred 5 minutes. A sodiumhypochlorite solution (5.25%, 2 mL) was added. The reaction was stirredat room temperature overnight. The aqueous portion was extracted 4 timeswith dichloromethane. The combined organic portions were washed withbrine, dried over magnesium sulfate and concentrated. Chromatography ofthe crude mixture on a Biotage Flash 40S column eluting with ethylacetate/hexane 1:5 gave the title compound (66 mg, 14%). MS (CI)m/z604.5 (M−1), 505.9 (M−99)

C. 2-tert-Butoxycarbonylamino-pent-4-ynoic acid methyl ester

Potassium carbonate (1.687 g, 12.2 mmol) was added to an anhydrousmethanol (91.5 mL) solution of 2-tert-butoxycarbonylamino-4-oxo-butyricacid benzyl ester (1.875 g, 6.10 mmol) and the reaction stirred 10minutes. (1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (1.407 g,7.32 mmol) was added and the reaction was stirred at room temptemperature 1 hour. The reaction was poured into diethyl ether andwashed 4 times with 5% sodium bicarbonate, dried over magnesium sulfateand concentrated (1.05 g, crude product mixture). The crude product wasused directly in the next step. ¹H NMR (400 MHz, CDCl₃) δ5.39 -5.31 (m,1H), 4.49-4.41 (m, 1H), 3.77 (s, 3H), 2.79-2.65 (m, 2H), 2.03 (s, 1H),1.59 and 1.44 (2 singlets, rotamers, 3H).

D. 2-tert-Butoxycarbonylamino-4-oxo-butyric acid benzyl ester

A dimethyl sulfoxide (10 mL) solution of2-tert-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (13.58 g,43.9 mmol) and triethyl amine (18.35 mL, 131.7 mmol) was cooled to 0° C.Pyridine sulfur trioxide (21.0 g. 131.7 mmol) in dimethyl sulfoxide (80mL) was added in a steady stream. The cooling bath was removed and thereaction stirred 1.5 hours. The reaction was poured into 130 mL icewater and extracted with diethyl ether (2×180 mL and 100 mL). Thecombined organic portion was washed sequentially with saturated sodiumbicarbonate, water, brine and dried over magnesium sulfate. The solventwas removed in vacuo and the crude product was chromatographed on silicagel (900 mL) eluting with ethyl acetate/hexanes (1:4), to give the titlecompound as a clear, colorless oil (9.20 g, 70%). MS (CI) m/z 208.0(M−99).

EXAMPLE 7 A.2-Acetylamino-4-(3-{1-[2-(4-benzyloxy-phenyl)-acetylamino]-3-methyl-butyl}-isoxazol-5-yl)-propionicacid

A 1:2 methanol/tetrahydrofuran (9 mL) solution of2-acetylamino-4-(3-{1-[2-(4-benzyloxyphenyl)-acetylamino]-3-methyl-butyl}-isoxazol-5-yl)-propionicacid ethyl ester (92 mg, 0.17 mmol) was combined with 2M aqueous lithiumhydroxide(3 mL) at room temperature stirred for 3 hours. After thereaction was acidified to pH=1 with 1N hydrochloric acid, the aqueousportion was extracted with ethyl acetate (2×50 mL). The combined organicportions were dried over sodium sulfate, and concentrated to give2-acetylamino-4-(3-{1-[2-(4-benzyloxy-phenyl)-acetylamino]-3-methyl-butyl}-isoxazol-5-yl)-propionicacid as a white crystalline solid (83 mg, 95%). MS (CI) m/z 508.1 (M+1),506.1 (M−1).

B.2-Acetylamino-4-(3-{1-[2-(4-benzyloxy-phenyl)-acetylamino]-3-methyl-butyl}-isoxazol-5-yl)-propionicacid ethyl ester

A solution of (4-benzyloxy-phenyl)-acetic acid (125 mg, 0.29 mmol, 1.00equivalents) and 1-hydroxybenzotriazole hydrate (48 mg, 0.36 mmol, 1.23equivalents) in dimethyl formamide (5 mL) was stirred at roomtemperature for 15 minutes.1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (64 mg, 0.33 mmol, 1.15equivalents) was added and the reaction was stirred for 15 minutes.2-Acetylamino-3-[3-(1-amino-3-methyl-butyl)-isoxazol-5-yl]-propionicacid ethyl ester hydrochloride (100 mg, 0.29 mmol, 1.00 equivalents) wasadded and the reaction was stirred for 25 minutes Triethylamine (43 μl,0.31 mmol, 1.07 equivalents) was added. The reaction was stirred at roomtemperature overnight then diluted with ethyl acetate (30 mL) andextracted with 1N hydrochloric acid (2×30 mL), saturated sodiumbicarbonate (2×30 mL) and brine (30 mL). The organic portion was driedover sodium sulfate and the solvent was removed in vacuo. The residuewas chromatographed on a 40S Biotage column (ethyl acetate) to give thetitle compound as a clear colorless oil (94 mg, 61%). MS (CI) m/z 536.2(M+1).

C. 2-Acetylamino-3-[3-(1-amino-3-methyl-butyl)-isoxazol-5-yl]-propionicacid ethyl ester hydrochloride

2-Acetylamino-3-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-yl]-propionicacid ethyl ester (7F) (5.95 g, 14.5 mmol) was stirred in 4N hydrochloricacid in dioxane (25 mL) at room temperature overnight. The product wasconcentrated and dried under high vacuum to give the title compound as awhite solid (5.38 g, 100%). MS (CI) m/z 312.2 (M+1 for the free base).

D. (4-Benzyloxy-phenyl)-acetic acid

A 1:2 methanol/tetrahydrofuran (60 mL) solution of(4-benzyloxy-phenyl)-acetic acid methyl ester (1.35 g, 5.27 mmol) wascombined with 2M aqueous lithium hydroxide (20 mL) at room temperatureand the reaction was stirred overnight. The reaction was acidified to pH1 with 1N hydrochloric acid and extracted with ethyl acetate (2×50 mL).The organic portions were dried over sodium sulfate and the solventremoved in vacuo to give the title compound as a white crystalline solid(1.25 g, 98%). ¹H NMR (300 MHz, CDCl₃) δ3.63 (s, 2H), 5.09 (s, 2H),6.96-6.99 (d, 2H), 7.22-7.25 (d, 2H), 7.3-7.5 (m, 5H).

E. (4-Benzyloxy-phenyl)-acetic acid methyl ester

Cesium carbonate (5.35 g, 16.4 mmol, 3.00 equivalents) was added to asolution of methyl 4-hydroxyphenylacetate (1.00 g, 6.02 mmol, 1.10equivalents) and benzyl bromide (0.65 mL, 5.47 mmol, 1.00 equivalents)in dichloromethane (40 mL) at 0° C. The mixture was allowed to warm toroom temperature and stirred vigorously overnight. The reaction wasextracted with 1N hydrochloric acid (2×100 mL) and brine (100 mL). Theorganic portion was dried over sodium sulfate and the solvent removed invacuo. The resulting oily solid was chromatographed on a 40S Biotagecolumn (20% ethyl acetate/Hexanes) to give the title ester as a clearcolorless oil (1.35 g, 96%). ¹H NMR (400 MHz, CDCl₃) δ3.56 (s, 2H), 3.67(s, 3H), 5.04 (s, 2H), 6.91-6.94 (d, 2H), 7.17-7.19 (d, 2H), 7.3-7.4 (m,5H).

F.2-Acetylamino-3-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-yl]-propionicacid ethyl ester

Sodium hydroxide,1N, (20.5 mL, 20.5 mmol, 1.10 equivalents) was added toa dioxane solution of2-acetylamino-2-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-ylmethyl]-malonicacid diethyl ester (8.99 g, 18.6 mmol, 1.0 equivalents) at roomtemperature over 30 minutes and the reaction was stirred overnight. Thereaction was diluted with ethyl acetate (200 mL) and acidified topH=1-1.5 with 1 N hydrochloric acid. The organic portion was washed withbrine (200 mL) and dried over sodium sulfate. The solvent was removed invacuo to give 8.58 9 of a 1:1 mixture (by ¹H NMR) of2-Acetylamino-2-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-ylmethyl]-malonicacid monoethyl ester [MS (CI) m/z 356.3 (M−99)] and the decarboxylatedtitle compound [MS (Cl) m/z 412.3 (M+1), 312.2 (M−99), 410.3(M−1)].

The mixture was refluxed in dioxane (150 mL) overnight and concentratedto yield an orange oil that was chromatographed using a Biotage column(40M, 50% ethyl acetate/hexanes) to give the title compound as a thickorange solid (6.72 g, 88%). MS (CI) m/z412.3 (M+1), 312.2 (M−99).

G.2-Acetylamino-2-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-ylmethyl]-malonicacid diethyl ester

Cesium carbonate (18.28 g, 56.1 mmol, 3.0 equivalents)was added to adimethyl formamide (300 mL) solution of[1-(5-bromomethyl-isoxazol-3-yl)-3-methyl-butyl]-carbamic acidtert-butyl ester (6.48 g, 18.7 mmol, 1.00 equivalents) anddiethylacetamidomalonate (4.86 g, 22.4 mmol, 1.20 equivalents) at 0° C.The mixture was stirred at room temperature for 5 hours. The reactionwas poured into diethyl ether (200 mL) and extracted with water (5×200mL) and brine (200 mL). The organic portion was dried over sodiumsulfate and the solvent was removed in vacuo to give the title compoundas a viscous oil (8.99 g, 99.4%). MS (CI) m/z484.0 (M+1), 384.1 (M−99).

H. [1-(5-Bromomethyl-isoxazol-3-yl)-3-methyl-butyl]-carbamic acidt-butyl ester

N-Chlorosuccinimide (5.80 g, 43.4 mmol, 1.00 equivalents);[1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid tert-butyl ester(10.00 g, 43.4 mmol, 1.00 equivalents) and pyridine (0.70 mL) werestirred in chloroform (70 mL) at room temperature for 1 hour. Propargylbromide (4.83 mL, 54.3 mmol, 1.25 equivalents) was added and thereaction was heated to 45° C. Triethylamine (6.35 mL, 45.6 mmol, 1.05equivalents) was added dropwise over 20 minutes at 45° C. The reactionwas stirred for an additional 1 hour, then it was diluted with water(200 mL) and extracted with dichloromethane (2×200 mL). The combinedorganic extracts were washed with saturated sodium bicarbonate (2×200mL) and brine (200 mL). The organic portion was dried over sodiumsulfate. Evaporation of the solvent gave a brown residue that waschromatographed by flash chromatography on silica gel to give the titlecompound as a white solid (6.48 g, 43%). MS (CI) m/z 247.0 (M−99)

I. 1-(Hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid tert-butylester

A mixture of (1-formyl-3-methyl-butyl)-carbamic acid tert-butyl ester(2.13 g), hydroxylamine hydrochloride (0.71 g, 10.2 mmol) and NaOAc (2g, 24.4 mmol) in MeOH (20 mL) and water (20 mL) was stirred vigorously.After 24 h the mixture was diluted with water (60 mL) and extracted withEtOAc (50 mL×3). The combined organics were washed with water and brine;dried over MgSO4; filtered and concentrated under reduced pressure.Purification by Flash 40 chromatography using a silica gel column andeluting with 15-25% EtOAc/hexane gave 1.5 g of the title compound as awhite solid. MP 156-157° C.

EXAMPLE 8 A.2-Allyloxycarbonylamino-3-[3-(1-benzoyl-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid

The hydrolysis of 8B was carried out according to the protocol inexample 1A to afford the title compound. MS (CI) m/z 414.2 (M+1), 412.2(M−1).

B.2-Allyloxycarbonylamino-3-[3-(1-benzoyl-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid ethyl ester

Benzoyl chloride (21 μl, 0.18 mmol, 1.0 equivalents) was added in oneportion to a solution of2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionicacid ethyl ester hydrochloride (1C) (74 mg, 0.20 mmol, 1.1 equivalents)in pyridine (29 μl, 0.36 mmol, 2.0 equivalents) and dichloromethane (2mL) at 0° C. The reaction was stirred at room temperature for 4 hoursthen diluted with ethyl acetate (30 mL). The reaction was extracted with1N hydrochloric acid (30 mL) and brine (30 mL). The organic portion wasdried over sodium sulfate and concentrated in vacuo to give the titlecompound (66 mg, 84%). MS (CI) m/z 442.3 (M+1).

EXAMPLE 9 A.2-Allyloxycarbonylamino-3-{3-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-yl]-isoxazol-5-yl}-propionicacid

The hydrolysis of 9B was carried out using the protocol in example 1A toafford the title compound MS (CI) m/z 490.0 (M+1), 487.8 (M−1).

B.2-Allyloxycarbonylamino-3-{3-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-yl]-isoxazol-5-yl}-propionicacid ethyl ester

Prepared using the same method described in example 8B. MS (CI) m/z518.0 (M+1).

EXAMPLE 10 A.2-Acetylamino-3-(3-{3-methyl-1-[2-(4-naphthalen-2-yl-phenyl)-acetylamino]-butyl}-isoxazol-5-yl)-propionicacid

The hydrolysis of 10B was carried out using the protocol in example 1Ato afford the title compound MS (CI) m/z 528.0 (M+1), 525.8 (M−1).

B.2-Acetylamino-3-(3-{3-methyl-1-[2-(4-naphthalen-2-yl-phenyl)-acetylamino]-butyl}-isoxazol-5-yl)-propionicacid

Prepared from (4-Naphthalen-2-yl-phenyl)-acetic acid in the mannerdescribed for example 7B.

C. (4-Naphthalen-2-yl-phenyl)-acetic acid

Lithium hydroxide, 2M, (3.0 mL) was added to a 2:1tetrahydrofuran:methanol (9.0 mL) solution of(4-Naphthalen-2-yl-phenyl)-acetic acid methyl ester (270 mg, 0.977mmol). The resulting mixture was stirred at room temperature for 1 hour.The reaction was acidified to pH=1 with 1M hydrochloric acid andextracted twice with ethyl acetate. The combined organic portions werewashed with brine, dried over magnesium sulfate and concentrated invacuo to give the title compound as a white solid (233mg, 91%). ¹H NMR(400 MHz, CDCl₃) δ8.01-7.39 (m, 11H), 3.72 (s, 2H)

D. (4-Naphthalen-2-yl-phenyl)-acetic acid methyl ester

Tetrakis triphenyphosphine palladium (65 mg, 7.4 mol %) was added to adimethoxy ethane (5.4 mL) solution of(4-Trifluoromethanesulfonyloxy-phenyl)-acetic acid methyl ester (447 mg,1.5 mmol), 2-naphthaleneboronic acid (286 mg, 1.67 mmol) and cesiumfluoride (505 mg, 3.33 mmol). The reaction was flushed with nitrogen andheated in an oil bath to 100° C. while stirring for 3 hours. Thereaction was then diluted with ethyl acetate and extracted with water,1M sodium hydroxide, water and brine. The organic portion was dried overmagnesium sulfate and concentrated in vacuo. The resulting residue waschromatographed on a Biotage Flash 40S column eluting with 5% ethylacetate in hexanes to give the title compound as a clear oil (273 mg,66%). ¹H NMR (400 MHz, CDCl₃) δ8.01-7.38 (m, 11H), 3.72 (s, 3H), 3.69(2H)

E. (4-Trifluoromethanesulfonyloxy-phenyl)-acetic acid methyl ester

Trifluoromethane sulfonic anhydride (32.2 mmol) was added dropwise over5 minutes to a −40° C. pyridine (70 mL) solution of(4-hydroxy-phenyl)-acetic acid methyl ester (5.35 g, 32.2 mmol). Thereaction was stirred at −40° C. for 10 minutes and then at 0° C. for 2hours. The reaction was diluted with diethyl ether and washed with waterand 2N hydrochloric acid. The organic portion was dried over magnesiumsulfate and concentrated in vacuo. The crude residue was chromatographedon a Biotage Flash 40M column eluting with ethyl acetate/hexanes (1:4)to provide the title compound as a clear, colorless oil, whichcrystallized upon standing 9.27 g, 97%). ¹H NMR (400 MHz, CDCl₃)δ7.37-7.34 (m, 2H), 7.24-7.21 (m, 2H), 3.70 (3H), 3.64 (2H).

EXAMPLE 11 A.2,2-Dimethyl-3-[3-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-propionicacid

The hydrolysis of 11B was carried out using the protocol in example 1Ato afford the title compound MS (CI) m/z: 521.2 (M+1), 519.1 (M−1)

B.2,2-Dimethyl-3-[3-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-propionicacid methyl ester

Prepared from3-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-yl]-2,2-dimethylpropionicacid methyl ester in two steps by following the procedure outlined inexamples 1C and 2B. MS (CI) m/z: 535.1 (M+1), 535.1 (M−1)

C.3-[3-(1-tert-Butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-yl]-2,2-dimethyl-propionicacid methyl ester

Prepared from [1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acidtert-butyl ester (7I) and 2,2-dimethyl-pent-4-ynoic acid methyl esteraccording to the procedure outlined in example 6A. MS (CI) m/z: 313.2(M-tBu), 269.3 (M−99)

EXAMPLE 12 A.3-[3-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-2-phenyl-propionicacid

The hydrolysis of 12B was carried out using the protocol in example 1Ato afford the title compound.

B.3-[3-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-2-phenyl-propionicacid methyl ester

The title compound was prepared from3-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-yl]-2-phenyl-propionicacid methyl ester in the manner described in example 11B.

C.3-[3-(1-tert-Butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-yl]-2-phenyl-propionicacid methyl ester

The title compound was prepared from 2-phenyl-pent-4-ynoic acid methylester in the manner described in example 6A.

D. 2-Phenyl-pent-4-ynoic acid methyl ester

Diisopropyl ethyl amine (5.9 mL, 42 mmol) was dissolved intetrahydrofuran (30 mL). Butyllithium, 2.5 M in hexanes, (16.8 mL, 42mmol) was added slowly at A solution of phenyl acetic acid (2.72 g, 20mmol) in tetrahydrofuran (20 mL) was added slowly via a dropping funnelover 20 minutes. The reaction was stirred for 25 minutes. Propargylbromide was added as an 80% weight solution in toluene (2.3 mL, 21.0mmol). The reaction was stirred for 1.5 hours and 4N hydrochloric acid(15 mL) was added. The mixture was diluted with ethyl acetate (50 mL).The organic portion was concentrated in vacuo. The residue was dissolvedin diethyl ether and extracted with water (3×) and 1 N hydrochloric acid(3×). The organic portion was dried over magnesium sulfate and thesolvent removed in vacuo. The resulting yellow solid (1.7 g) wasdissolved in methanol (50 mL) and cooled to 0C. Acetylchloride (2 mL)was added and the reaction was allowed to warm to room temperature.After the reaction stirred for 18 hours, the solvent was removed invacuo. The residue was dissolved in diethyl ether. The solution wasextracted with saturated sodium bicarbonate, water, and brine. Theorganic portion was dried over magnesium sulfate and the solvent removedin vacuo. The residue was chromatographed on silica gel with 10% ethylacetate in hexanes to give the title compound as an oil (0.58 g, 15%)

EXAMPLE 13 A.2-Acetylamino-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid

The hydrolysis of 13B was carried out using the protocol in example 1Ato afford the title compound. MS (CI) m/z 534.2 (M+1), 532.4 (M−1).

B.2-Acetylamino-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5yl]-propionicacid ethyl ester

The title compound was prepared from2-[5-(2-acetylamino-2-methoxycarbonyl-ethyl)-isoxazol-3-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester as described in example 11B. MS (CI) m/z 562.1(M+1).

C.2-[5-(2-Acetylamino-2-methoxycarbonyl-ethyl)-isoxazol-3-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

The title compound was prepared from the2-(hydroxyimino-methyl)-pyrrolidine-1-carbamic acid tert-butyl ester andthe 2-acetylamino-pent-4-ynoic acid methyl ester as described in example6B. MS (CI) m/z 296.0 (M−99)

EXAMPLE 14 A.2-(2,6-Dichloro-benzoylamino)-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid

The hydrolysis of 14B was carried out using the protocol in example 1Ato afford the title compound. MS (CI) m/z 663.8 (M+1).

B.2-(2,6-Dichloro-benzoylamino)-3-[3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid ethyl ester

The title compound was prepared from2-{5-[2-(2,6-dichloro-benzoylamino)-2-ethoxycarbonyl-ethyl]-isoxazol-3-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester in a manner similar to that described in 11B. MS(CI) m/z 691.8 (M+1), 689.7 (M−1).

C.2-{5-[2-(2,6-Dichloro-benzoylamino)-2-ethoxycarbonyl-ethyl]-isoxazol-3-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester

The title compound was prepared from2-[5-(2-amino-2-ethoxycarbonyl-ethyl)-isoxazol-3-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester hydrocloride and 2,6-dichlorobenzoylchloride inthe manner described in example 3B. MS (CI) m/z 525.9 (M+1), 425.9(M−99).

D.2-[5-(2-Amino-2-ethoxycarbonyl-ethyl)-isoxazol-3-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester hydrocloride

2-{5-[2-(Benzhydrylidene-amino)-2-ethoxycarbonyl-ethyl]-isoxazol-3-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (700 mg, 1.35 mmol) was stirred in a mixture ofethyl acetate (20 mL) and 1N hydrochloric acid (100 mL) for 3 hours. Thereaction was neutralized by the addition of saturated sodiumbicarbonate. The aqueous portion was extracted with diethyl ether. Thecombined organics were dried over magnesium sulfate and the solventremoved in vacuo. The resulting oil (200 mg) was used directly inexample 14C.

E.2-{5-[2-(Benzhydrylidene-amino)-2-ethoxycarbonyl-ethyl]-isoxazol-3-yl}-pyrrolidine-carboxylicacid tert-butyl ester

2-(5-Bromomethyl-isoxazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butylester (1.0 g, 3 mmol) and N-(diphenylmethylene)glycine glycine ethylester (1.0 g, 3.74 mmol) were dissolved in toluene (10 mL). Aqueouspotassium hydroxide, 18M, (0.25 mL, 4.5 mmol) and tetrabutylammoniumbromide (97 mg, 0.30 mmol) were added. After the reaction was stirred atroom temperature for 1 hour, 1N hydrochloric acid was added (4.5 mL).The organic phase was extracted with 1N hydrochloric acid, saturatedsodium bicarbonate, and brine. The organic portion was dried overmagnesium sulfate and the solvent removed in vacuo. The residue waschromatographed with 15% ethylacetate in hexanes on a Biotage 40S columnto give the title compound (700 mg, 45%). MS (CI) m/z 518.0 (M+1).

EXAMPLE 15 A.2-Allyloxycarbonylamino-3-{3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-isoxazol-5-yl)-propionicacid

The hydrolysis of 15B was carried out using the protocol in example 1Ato afford the title compound. MS (CI) m/z 464.0 (M+1), 461.9 (M−1).

B.2-Allyloxycarbonylamino-3-{3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-isoxazol-5-yl}-propionicacid ethyl ester

The title compound was prepared according to the method described inexample 1B. MS (CI) m/z 492.0 (M+1).

EXAMPLE 16 A.2-Allyloxycarbonylamino-3-[3-(1-{[4-(2,6-dimethoxy-benzoylamino)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid

The hydrolysis of 16B was carried out using the protocol in example 1Ato afford the title compound. MS (CI) m/z 606.7 (M+1), 605.1 (M−1).

B.2-Allyloxycarbonylamino-3-[3-(1-{[4-(2,6-dimethoxy-benzoylamino)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid ethyl ester

The title compound was prepared according to the procedure described inexample 3B, using 2,6-dimethoxybenzoylchloride in place of2,6-dichlorobenzoylchloride. MS (CI) m/z 635.3 (M+1), 632.5 (M−1)

EXAMPLE 17 A.2-Allyloxycarbonylamino-3-{3-[1-(3,4-dimethoxy-benzenesulfonyl)-pyrrolidin-2-yl]-isoxazol-5-yl}-propionicacid

The hydrolysis of 17B was carried out using the protocol in example 1Ato afford the title compound. MS (CI) m/z 507.6 (M−1).

B.2-Allyloxycarbonylamino-3-{3-[1-(3,4-dimethoxy-benzenesulfonyl)-pyrrolidin-2-yl]-isoxazol-5-yl}-propionicacid ethyl ester

The title compound was prepared according to the method described inexample 1B, using 3,4-dimethoxybenzenesulfonylchloride. MS (CI) m/z537.8 (M+1).

EXAMPLE 18 A.2-Allyloxycarbonylamino-3-[3-(1-cyclopropanecarbonyl-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid

The hydrolysis of 18B was carried out using the protocol in example 1Ato afford the title compound. MS (CI) m/z 378.2 (M+1), 376.2 (M−1).

B.2-Allyloxycarbonylamino-3-[3-(1-cyclopropanecarbonyl-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid ethyl ester

The title compound was prepared according to the method described inexample 3B using the appropriate reagents. MS (CI) m/z 406.1 (M+1).

EXAMPLE 19 A.2-Acetylamino-3-[3-(3-methyl-1-{2-[4-(2-methyl-benzyloxy)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-propionicacid

The hydrolysis of 19B was carried out using the protocol in example 1Ato afford the title compound. MS (CI) m/z 508.1 (M+1), 506.1 (M−1).

B.2-Acetylamino-3-[3-(3-methyl-1-(2-[4-(2-methyl-benzyloxy)-phenyl]acetylamino}-butyl)-isoxazol-5-yl]-propionicacid ethyl ester

The title compound was prepared according to the method described inexample 7B, using [4-(2-methyl-benzyloxy)-phenyl]-acetic acid. MS (CI)m/z 550.2 (M+1).

B. [4-(2-Methyl-benzyloxy)-phenyl]-acetic acid

The title compound was prepared according to the method described inexample 7D. ¹H NMR (300 MHz, CDCl₃) δ2.40 (s, 3H), 3.65 (s, 2H), 5.05(s, 2H), 6.98-7.01 (d, 2H), 7.02-7.30 (m, 5H), 7.42-7.44 (d, 1H).

D. [4-(2-Methyl-benzyloxy)-phenyl]-acetic acid methyl ester

The title compound was prepared according to the method described inexample 7E. ¹H NMR (400 MHz, CDCl₃) δ2.35 (s, 3H), 3.56 (s, 2H), 3.67(s, 3H), 5.00 (s, 2H), 6.92-6.94 (d, 2H), 7.18-7.26 (m, 5H), 7.37-7.39(d, 1H).

EXAMPLE 20 A.2-Acetylamino-3-(3-{1-[2-(4′-ethyl-biphenyl-4-yl)-acetylamino]-3-methyl-butyl}-isoxazol-5-yl)-propionicacid

The hydrolysis of 20B was carried out using the protocol in example 1Ato afford the title compound. MS (CI) m/z 506.1 (M+1), 504.0 (M−1).

B.2-Acetylamino-3-(3-{1-[2-(4′-ethyl-biphenyl-4-yl)-acetylamino]-3-methyl-butyl}isoxazol-5-yl)-propionicacid ethyl ester

The title compound was prepared according to the method described inexample 7B, using (4′-ethyl-biphenyl-4-yl)-acetic acid. MS (CI) m/z534.2 (M+1).

C. (4′-Ethyl-biphenyl-4-yl)-acetic acid

The title compound was prepared according to the method described inexample 10B MS (CI) m/z 239.0 (M−1).

D. (4′-Ethyl-biphenyl-4-yl)-acetic acid methyl ester

The title compound was prepared according to the method described inexample 10C. ¹H NMR (400 MHz, CDCl₃) δ7.63(d, J=8.1 Hz, 2H), 7.60 (d,J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 3.79 (s,3H), 3.75 (s, 3H), 2.78 (q, J=7.5 Hz, 2H), 1.37 (t, J=7.5 Hz, 3H).

EXAMPLE 21 A.2-Acetylamino-3-(3-{1-[(4-benzyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionicacid

The title compound was prepared from2-acetylamino-2-(3-{1-[(4-benzyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-ylmethyl)-malonicacid diethyl ester using the method of example 1D. MS (CI) m/z492.2(M+1), 490.3 (M−1)

B.2-Acetylamino-2-(3-{1-[(4-benzyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-ylmethyl)-malonicacid diethyl ester

MS (Cl) m/z 602.0 (M+1)

EXAMPLE 22 A.2-Acetylamino-3-[3-(1-{[4-(4-chloro-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid

The title compound was prepared from 22B according to the methoddescribed in example 21A. MS (CI) m/z 526.2 (M+1), 524.2 (M−1).

B.2-Acetylamino-3-[3-(1-{[4-(4-chloro-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl]-isoxazol-5-ylmethyl)-malonicacid diethyl ester

The title compound was prepared according to the method described inexample 21B, using [4-(4-chloro-benzyloxy)-phenyl]-acetic acid. MS (CI)m/z 626.0 (M+1).

C. [4-(4-Chloro-benzyloxy)-phenyl]-acetic acid

The title compound was prepared according to the method described inexample 7D. ¹H NMR (400 MHz, dimethyl sulfoxide) δ3.44 (s, 2H), 5.05 (s,2H), 6.88-6.92 (m, 2H), 7.11-7.14 (m, 2H), 7.42 (s, 4H), 12.20 (s, 1H).¹³C NMR (100 MHz, dimethyl sulfoxide) δ68.9, 115.2, 128.1, 129.1, 130.1(2 overlapping peaks), 131.1, 133.0, 136.9, 157.5, 173.6.

D. [4-(4-Chloro-benzyloxy)-phenyl]-acetic acid methyl ester

The title compound was prepared according to the method described inexample 7E. ¹H NMR (400 MHz, CDCl₃) δ3.55 (s, 2H), 3.67 (s, 3H), 5.00(s, 2H), 6.88-6.90 (d, 2H), 6.88-6.90 (d, 2H), 1.17-7.19 (d, 2H), 7.34(s, 4H).

EXAMPLE 23 A.2-Acetylamino-3-[3-(1-{[4-(3-phenyl-allyl)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionicacid

The title compound was prepared from 23B according to the methoddescribed in example 22A. MS (CI) m/z 502.2 (M+1), 500.2 (M−1)

B.2-Acetylamino-3-[3-(1-{[4-(3-phenyl-allyl)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-ylmethyl)-malonicacid diethyl ester

The title compound was prepared from [4-(3-phenyl-allyl)-phenyl]-aceticacid according to the method described in example 22B. MS (CI) m/z 602.0(M+1).

C. [4-(3-Phenyl-allyl)-phenyl]-acetic acid

The title compound was prepared from [4-(3-phenyl-allyl)-phenyl]-aceticacid according to the method described in example 10B. ¹H NMR (400 MHz,CDCl₃) δ3.51 (d, 2H, J=7 Hz), 3.62 (s, 2H), 6.28-6.46 (m, 2H), 7.18-7.37(m, 9H).

D. [4-(3-Phenyl-allyl)-phenyl]-acetic acid

(4-Trifluoromethanesulfonyloxy-phenyl)-acetic acid methyl ester (500 mg,1.68 mmol, 1.00 equivalents), palladium (II) chloride (15 mg, 5 mol %),bis-diphenylphosphinoethane (50 mg, 5 mol %), bis(pinacolato)diboron(469 mg, 1.85 mmol, 1.10 equivalents), and potassium acetate (495 mg,5.04 mmol, 3.00 equivalents) were heated in dimethyl formamide (10 mL)at 80° C. for 3 hours. The black reaction mixture was cooled to roomtemperature. Palladium (II) chloride (15 mg, 5 mol %),bis-diphenylphosphinoethane (50 mg, 5 mol %), cinnamyl bromide (660 mg,3.35 mmol, 2.00 equivalents), sodium carbonate (890 mg, 8.40 mmol, 5.00equivalents), and water (4 mL) were added. The reaction mixture washeated to 80° C. overnight. The reaction was cooled to room temperatureand diluted with ethyl acetate (50 mL). This mixture was extracted withsaturated sodium bicarbonate (2×50 mL), water (2×50 mL) and brine (50mL). The organic portion was dried over sodium sulfate. Evaporation ofthe solvent gave a black oily residue that was chromatographed onBiotage (5% ethyl acetate/hexanes) to give a 9:1 mixture of the titlecompound and acetic acid 3-phenyl-allyl ester (200 mg, 45%). ¹H NMR (400MHz, CDCl₃) δ3.52 (dd, 2H, J=7,1.2 Hz), 3.60 (s, 2H), 3.68 (s, 3H),6.24-6.38 (m, 1H), 6.43-6.47 (d, 1H), 7.1-7.4 (m, 9H). This material wasused in example 23C without further purification.

EXAMPLE 24 A.2-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-1H-benzoimidazole-4-carboxylicacid

The title compound was prepared from 24B according to the methoddescribed in example 1A. MS (CI) m/z 514.1 (M+1), 512.2 (M−1)

B.2-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-1H-benzoimidazole-4-carboxylicacid methyl ester

The title compound was prepared from 24C according to the methoddescribed in example 2B. MS (CI) m/z 528.0 (M+1), 526.2 (M−1)

C. 2-(1-Amino-3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid methylester hydrochloride

A solution of4-Amino-3-(2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-benzoicacid methyl ester (690 mg, 1.82 mmol) in acetic acid (9 mL) was heatedto 70° C. with stirring for 1.5 hours. The acetic acid was removed invacuo and the crude mixture was dissolved up in 4M hydrochloric acid indioxane (9 mL) and stirred at room temperature for 30 minutes. Thereaction was concentrated in vacuo to give the title compound. MS (CI)m/z 262.0 (M+1), 260.1 (M−1)

E.4-Amino-3-(2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-benzoicacid methyl ester

Hydroxybenzotriazole monohydrate (760 mg, 5.62 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride (973 mg, 5.07mmol) were added to a dimethyl formamide (30 mL) solution ofN-tert-butoxycarbonyl-L-leucine (1.06 g, 4.57 mmol). The mixture wasstirred until all 1-(3-dimethylaminopropyl)-3-ethylcarbodiimdehydrochloride had dissolved. Methyl 3,4-diaminobenzoate (759 mg, 4.57mmol) in dimethyl formamide (10 mL) and triethyl amine (0.68 mL, 4.89mmol) were added sequentially. The reaction was stirred at roomtemperature over night and poured into water. This mixture was extractedwith ethyl acetate three times. The organic portion was extracted with asaturated solution of sodium bicarbonate, water (2×) and brine. Theorganic portion was dried over magnesium sulfate and the solvent removedin vacuo. The resulting residue was chromatographed on a Biotage Flash40S column eluting with ethyl acetate/hexanes (2:3) which yielded thetitle compound (690 mg, 40%). MS (CI) m/z 380.0 (M+1), 378.2 (M−1).

EXAMPLE 25 A.2-(2,6-Dichloro-benzoylamino)-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionicacid

A mixture of 25B (56 mg, 0.13 mmol) in tert-butanol (1 mL) and 1N sodiumhydroxide (0.27 mL) was stirred at reflux. After 30 minutes the mixturewas concentrated under reduced pressure, and the resulting residue wasdissolved in water and washed with ethyl acetate. The aqueous layer wasacidified to pH 1 with 1N HCl and extracted into ethyl acetate. Thecombined organic layers were washed with water and brine, dried oversodium sulfate and concentrated under reduced pressure to give anoff-white solid. MP 102-4° C.; MS (m/z) 710.3 and 713.3 (M+1).

B.2-(2,6-Dichloro-benzoylamino)-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionicacid methyl ester

The title compound was prepared in the manner described in example 2Busing 3-methoxy-4-(3-o-tolyl-ureido)-phenylacetic acid and3-[3-(1-amino-3-methyl-butyl)-isoxazol-5-yl]-2-(2,6-dichloro-benzoylamino)-propionicacid methyl ester hydrochloride. 51% yield; white solid. MS (m/z) 724.2and 726.2 (M+1).

C.3-[3-(1-Amino-3-methyl-butyl)-isoxazol-5-yl]-2-(2,6-dichloro-benzoylamino)-propionicAcid Methyl Ester Hydrochloride

The title compound was prepared from 25D in the same manner as example1C. MS (m/z) 428.3 and 430.3 (M+1).

D.3-[3-(1-tert-Butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-yl]-2-(2,6-dichloro-benzoylamino)-propionicacid methyl ester

The title compound was prepared from 25E and 71 in the same manner asexample 7H. MS (m/z) 526.2 and 528.0 (M-1).

E. 2-(2,6-Dichloro-benzoylamino)-pent-4-ynoic acid methyl ester

The title compound was prepared from 2-amino-pent-4-ynoic acid methylester and 2,5-dichlorobenzoyl chloride in the same manner as example 3B.MS (m/z) 300.2 and 302.2 (M+1).

EXAMPLE 26 A.2-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-ylmethyl]-4-methyl-pentanoicAcid

The title compound was prepared in the same manner as Example 25, stepsA-D, using 4-methyl-2-propargyl pentanoic acid methyl ester in step D.MS (m/z) 577.3 (M−1).

EXAMPLE 27 A.2-acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionicacid

The title compound was prepared in the same manner as Example 7A and B.using 3-methoxy-4-(3-o-tolyl-ureido)-phenylacetic acid in part B. Whitesolid; MP 123-5° C.; MS (m/z) 578.1 (M−1).

EXAMPLE 28 A.2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-methyl]-phenyl}-propionicacid

The title compound was prepared in the same manner as example 25, stepsA and B. using 28B in step 25B. MS (m/z) 633 (M+1).

B. 2-Acetylamino-2-[(3-aminomethyl-phenyl)-methyl]-malonic acid diethylester

A mixture of 28C (1.15 g, 3.5 mmol), 10% Pd on carbon (0.15 g) andconcentrated HCl (0.3 mL) in ethanol (50 mL) was placed on a Parr shakerapparatus under 45 p.s.i. hydrogen for 6 hours. The mixture was filteredthrough celite and concentrated under reduced pressure to give 1.2 g ofthe title compound as a white solid. MS (m/z) 337.3 (M+1).

C. 2-Acetylamino-2-[(3-cyanophenyl)-methyl]-malonic acid diethyl ester

The title compound was prepared from alpha-bromo-meta-tolunitrile in thesame manner as example 7G. MS (m/z) 333 (M+1).

EXAMPLE 29 Binding of Biotinylated CS-1 to Isolated VLA-4

The VLA-4/bCS-1 receptor ligand binding assay described herein tests theability of a compound to specifically inhibit VLA-4 dependent binding.

A. Preparation of VLA-4 Coated Plates

VLA-4 coated plates were prepared the day before the assay was carriedout. The VLA-4-expressing stock was isolated from Jurkat cells accordingto the protocol of Makarem et al., J. Biol. Chem., 269, 4005-4011 (1994)and was diluted in 50 mM NaHCO₃ (pH 8.8) to a final concentration of 0.4mg/ml. Aliquots of 100 ml of this stock solution were then added to eachwell of a 96 well Microfluor “B” U-bottom plate (Dynatech No.0010107205) and incubated overnight at 4° C. The coating solution wasremoved by aspiration and the wells were quenched for 0.5 hour with PBSplus 1 mM MnCl containing 1% non-fat dry milk (200 ml/well, 37° C). Thedry milk was removed by aspiration immediately before addition of thebiotinylated CS-1.

B. Binding of Biotinylated CS-1 to Isolated VLA-4

The biotinylated CS-1 peptide (bCS-1) was prepared. This peptide wasdiluted with PBS plus 1 mM MnCl containing 0.1% non-fat dry milk (PBSB)to a final concentration of 5 mg/ml. Aliquots of 200 ml are added to thewells of a 96 well polypropylene transfer plate containing compounds(32, 10, 3.2,1, 0.32 and 0.1 mM), vehicle or antibodies (0.5 mg/ml) inPBSB containing 0.1% DMSO for 60 min (37° C.). The plate is washed threetimes with 200 ml/well of PBSB to remove unbound bCS-1. Following this,100 ml of a 1:5000 dilution of streptavidin poly-HRP in PBSB was addedto each well for 60 min (37° C.). Unbound streptavidin poly-HRP wasremoved by aspiration and the plate was washed three times with PBSB(200 ml/well). Following the final wash, 100 ml of TMB substrate wasadded to each well to react with the bound streptavidin poly-HRP and theOD of each well on the plate was determined on the Emax plate reader(650). The results were based on the mean of duplicate determinations.

EXAMPLE 30 VLA-4 Dependent THP1 Cell Binding to Baculovirus sVCAM

The THP1 baculovirus sVCAM cell binding assay tests the ability of acompound to inhibit VLA-4 dependent binding to sVCAM.

A. Preparation of sVCAM Coated Plates

The baculovirus sVCAM coated plates were prepared the day before theexperiment was carried out. The baculovirus sVCAM stock from PanVera wasdiluted in 50 mM NaHCO₃ (pH 8.8) to a final concentration of 5 mg/ml.Aliquots of 50 ml of this stock solution were then added to each well ofa 96 well Microfluor “B” U bottom plate (Dynatech No. 0010107205) andincubated overnight (4° C.). The coating solution was removed byaspiration and the wells were quenched for 1 hour with PBS containing 5%non-fat dry milk (150 ml/well, 4° C.). The dry milk is removed by shockdumping immediately before addition of the biotinylated CS-1.

B. Labeling and Binding of THP1 Cells

THP1 cells were obtained from the American Type Culture Collection(ATCC, Rockville, Md.) and grown in RPMI 1640 media containing 10% 1 mMMnCl₂ for 20 min (37° C.). Following MnCl₂ activation, the cells werespun down (approximately 500 g for 5 min) and resuspended twice in serumfree basal media (EBM, 37° C.). The cells in serum free media (2×10⁶/ml)were then incubated with 5 mM Calcein AM for 30 min at 37° C. Followinglabeling, all cells are spun down (approximately 500 g for 5 min) andresuspended twice in RPMI 1640 containing 10% FBS to cleave any freecalcein AM. The cells were then resuspended twice in DPBS (+1 mM CaCl₂and 1 mM MgCl₂) containing 1 mg/ml BSA (DPBSB) and diluted to 667,000cells/ml. Aliquots Of 200 ml were added to the wells of a 96 wellpolypropylene transfer plate containing test compounds (10, 5, 1 and 0.1mM), vehicle or antibodies (0.5 mg/ml) in DPBSB containing 0.1% DMSO for30 min (37° C.). The next 150 ml (100,000 cells) were removed from eachwell and transferred into appropriate wells of a quenched baculovirussVCAM coated plate for 45 min (37° C.). Unbound cells were removed byaspiration and the plate was washed three times with DPBSB (100ml/well). Following the final wash, 100 ml of DPBSB was added to eachwell and the plate was read on a Cytoflour II fluorescent plate reader.Three readings were taken per well at an excitation of 480 and emissionof 530. The results were based on the mean of duplicate determinations.The average background fluorescence of blank wells was subtracted fromeach sample to give a corrected fluorescence intensity value for eachsample.

What is claimed is:
 1. A compound of Formula (1.0.0)

and pharmaceutically acceptable salts and other prodrug derivativethereof, wherein: A is (C₁-C₆) alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl as defined herein; where said alkyl, cycloalkyl, aryl,heteroaryl or heterocyclyl is optionally substituted with 0 to 3 R⁹; oris a member selected from the group consisiting of the followingradicals: A¹-NHC(═O)NH-A²-, A¹-NHC(═O)O-A²-, A¹-OC(═O)NH-A²-,A¹-NHSO₂NH-A²-, A¹-NHC(═O)-A²-, A¹-C(═O)NH-A²-, A¹NHSO₂-A²-,A¹SO₂NH-A²-, A¹-(CH₂)_(r)O-A²-, A¹-O(CH₂)_(r)A²-, A¹-(CH₂)_(r)A², whereA¹ is aryl and A² is aryl or pyridyl: group is substituted with 0 to 3R⁹; B is a member independently selected from the group consisting ofthe following:

where the symbol “*” indicates the point of attachment of the moietyrepresented by each partial Formula (1.1.0) through (1.1.4), (1.1.6) and(1.1.8) to the moiety “CR²R³” in Formula (1.0.0); and the symbol “→”indicates the point of attachment of the moiety represented by eachpartial Formula (1.1.0) through (1.1.4), (1.1.6) and (1.1.8) to themoiety “E” in Formula (1.0.0); each of Formula (1.1.0) through (1.1.4),(1.1.6) and (1.1.8), may be optionally substituted with R⁹; E is asingle bond X is —O—; Y is —C(═O); k is an integer independentlyselected from 0, 1 and 2; m is an integer independently selected from 0and 1; n is an integer independently selected from 0, 1 and 2; p is 1; qis an integer independently selected from 0,1 and 2; r is an integerindependently selected from 0, 1 and 2; R² and R³ are each independentlyselected from the group consisting of hydrogen and (C₁-C₆) alkylsubstituted with 0 to 3 R¹³; R⁴ is hydrogen; or (C₁-C₆) alkyl optionallysubstituted with R¹³; R⁵ and R⁶ are independently hydrogen; (C₁-C₆)alkyl; (C₂-C₆) alkenyl; (C₂-C₆) alkynyl; CF₃; aryl; cycloalkyl;heteroaryl; or heterocyclyl; R⁷ is (C₁-C₆) alkyl; (CH₂)_(k)OR⁵;(CH₂)_(k)NR⁶C(═O)R⁵; (CH₂)_(k)NR⁶C(═O)OR⁵; (CH₂)_(k)NR⁶SO₂R⁵;(CH₂)_(k)NR⁶R⁵; F; CF₃; OCF₃; aryl, substituted with to 3 R⁹;heterocyclyl, substituted with 0 to 3 R⁹; heteroaryl, substituted with 0to 3 R⁹; cycloalkyl, substituted with 0 to 3 R⁷; or may be takentogether with R⁸ to for a cycloalkyl or heterocyclyl ring; or R⁷ may betaken together with R¹¹ to form a cycloalkyl or heterocyclyl ring; R⁸ ishydrogen; F; (C₁-C₆) alkyl or (C₁-C₆) alkoxy; R⁹ is halogen; (C₁-C₆)alkyl; (C₁-C₆) alkoxy; (C₃-C₆) cycloalkyl; (C₃-C₆) cycloalkoxy; cyano;(CH₂)_(k)OH; C(═O)R⁵; (CH₂)_(k)C(O)NR⁵R⁶; (CH₂)_(k)NR⁵R⁶;(CH₂)_(k)NR⁵SO₂R⁶; CF₃; OCF₃; SO₂NR⁵R⁶; (CH₂)_(m)C(═O)OR⁵; when R⁹ isattached to a saturated carbon atom R⁹ may be ═O or ═S; when R⁹ isattached to a sulphur atom R⁹ ma be ═O; R¹⁰ is hydrogen; C(═O)R⁵;C(═O)OR⁵; (C₁-C₆) alkyl; aryl; heterocyclyl; heteroaryl; cycloalkyl; orSO₂R⁵; R¹¹ and R¹² are independently hydrogen; (C₁-C₆) alkyl; hydroxy;cyano; (C₁-C₆) alkoxy; NR⁶C(═O)R⁵; NR⁶SO₂R⁵; NR⁶R⁵; CF₃; F; aryl;heterocyclyl; heteroaryl; cycloalkyl; cycloalkoxy; or R¹¹ may be takentogether with R¹² to for a cycloalkyl or heterocyclyl ring; and R¹³ isindependently selected from the group consisting of halogen; CF₃;(C₁-C₆) alkyl; aryl; heteroaryl; heterocyclyl; hydroxy; cyano; (C₁-C₆)alkoxy; (C₃-C₆) cycloalkyl; (C₃-C₆) cycloalkoxy; (C₂-C₆) alkynyl;(C₂-C₆) alkenyl; -NR⁶R⁵; —C(═O)NR⁵R⁶; SO₂R⁵; C(═O)R⁵; NR⁵SO₂R⁶;NR⁵C(═O)R⁶; C(═O)NR⁵SO₂R⁶; NR⁵C(═O)OR⁶; and SO₂NR⁶R⁵.
 2. A compoundaccording to claim 1 wherein A¹ and A² are both aryl.
 3. A compoundaccording to claim 2 wherein said aryl is phenyl, said phenyl andpyridyl being independently substituted by 0 or 1 substituent R⁹ whichis member selected from the group consisting of F; Cl; F₃C—; methyl;methoxy; hydroxy; iso-propyl; cyclopropyloxy; and cyclopentyl.
 4. Acompound according to claim 3, wherein n is the integer 1 resulting in amethylene bridge.
 5. A compound according to claim 4 wherein for thecomponent of Formula (1.0.0) which is -NR⁴CR²CR^(3-, R) ⁴ is hydrogen,R² is hydrogen, and R³ is iso-butyl.
 6. A compound according to claim 3wherein B is a member selected from the group consisting of partialFormulas (1.1.2) and (1.1.6)

where the symbol “*” and the symbol “″” are as previously defined.
 7. Acompound according to claim 6 where B is partial Formula (1.1.6).
 8. Acompound according to claim 1 wherein said compound is:3[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-5-yl]-2-methyl-propionicacid;2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-5-yl]-propionicacid;2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-5-yl]-propionicacid;2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}amino)-ethyl]-4,5-dihydro-oxazol-5-yl}-propionicacid;2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-5-yl}-propionicacid;2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-oxazol-5-yl)-propionicacid;2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-4,5-dihydro-oxazol-5-yl}-propionicacid; or2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-5-yl}-propionicacid.
 9. A compound according to claim 1 wherein said compound is:3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-4-yl]-2-methyl-propionicacid;2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-4-yl]-propionicacid;2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-4-yl]-propionicacid;2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}amino)-ethyl]-4,5-dihydro-oxazol-4-yl}-propionicacid;2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-4-yl}-propionicacid;2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-oxazol-4-yl)-propionicacid;2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}methyl-amino)-methyl]-5-methyl-4,5-dihydro-oxazol-4-yl}-propionicacid;2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-4-yl}-propionicacid.
 10. A compound according to claim 1 wherein said compound is:3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-5-yl]-2-methyl-propionicacid;2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-5-yl]-propionicacid;2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-5-yl]-propionicacid;2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}amino)-ethyl]-oxazol-5-yl}-propionicacid;2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenlI-acetyl}-methyl-amino)-methyl]-oxazol-5-yl}-propionic acid;2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-5-yl)-propionicacid;2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}methyl-amino)-methyl]-4-methyl-oxazol-5-yl}-propionicacid;2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-5-yl}-propionic acid. 11.A compound according to claim 1 wherein said compound is:3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-4-yl]-2-methyl-propionicacid;2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-4-yl]-propionicacid;2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-4-yl]-propionicacid;2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}amino)-ethyl]-oxazol-4-yl}-propionicacid;2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-4-yl}-propionicacid;2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-4-yl)-propionicacid;2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}methyl-amino)-methyl]-5-methyl-oxazol-4-yl}-propionicacid;2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-4-yl}-propionic acid. 12.A compound according to claim 1 wherein said compound is:3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-isooxazol-5-yl]-2-methyl-propionicacid;2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-isoxazol-5-yl]-propionicacid;2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-isoxazol-5-yl]-propionicaci2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}amino)-ethyl]-4,5-dihydro-isoxazol-5-yl}-propionicacid;2-Allyloxycarbonylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-isoxazol-5-yl}-propionicacid;2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-isoxazol-5-yl)-propionicacid;2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl{-methyl-amino)-methyl]-4-methyl-4,5-dihydro-isoxazol-5-yl}-propionicacid;2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-isoxazol-5-yl}-propionicacid.
 13. A compound according to claim 1 wherein said compound is:3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isooxazol-5-yl]-2-methyl-propionicacid;2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionicacid;2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionicacid;2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}amino)-ethyl]-isoxazol-5-yl}-propionicacid;2-Allyloxycarbonylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazol-5-yl}-propionicacid;2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-isoxazol-5-yl)-propionicacid;2-Formylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-isoxazol-5-yl}-propionicacid;2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazol-5-yl}-propionic acid.14. A compound according to claim 1 wherein said compound is:3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-2-methyl-propionicacid;2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-propionicacid;2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-propionicacid;2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}amino)-ethyl]-oxazol-2-yl}-propionicacid;2-Allyloxycarbonylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionicacid;2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-1)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-2-yl)-propionicacid;2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}methyl-amino)-methyl]-5-methyl-oxazol-2-yl}-propionicacid; or2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionic acid. 15.A pharmaceutical composition comprising a compound of Formula (1.0.0) asdefined in claim 1 together with a pharmaceutically acceptable carrierfor said compound.
 16. A method of treating an inflammatory, autoimmuneor respiratory disease by inhibiting cell adhesion and consequent orassociated pathogenic processes subsequently mediated by VLA-4,comprising administering to a mammal in need of such treatmenttherapeutically effective amount of a compound of Formula (1.0.0) asdefined in claim 1 or a pharmaceutical composition as defined in claim15.
 17. A method according to claim 16 wherein said inflammatory,autoimmune or respiratory disease is a member selected from the groupconsisting essentially of asthma, multiple sclerosis, rheumatoidarthritis, osteoarthritis, inflammatory bowel disease, psoriasis, hostrejection following organ transplantation, atherosclerosis, and otherdiseases mediated by or associated with VLA-4.